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1.  Thiamine Diphosphate in Whole Blood, Thiamine and Thiamine Monophosphate in Breast-Milk in a Refugee Population 
PLoS ONE  2012;7(6):e36280.
Background
The provision of high doses of thiamine may prevent thiamine deficiency in the post-partum period of displaced persons.
Methodology/Principal Findings
The study aimed to evaluate a supplementation regimen of thiamine mononitrate (100 mg daily) at the antenatal clinics in Maela refugee camp. Women were enrolled during antenatal care and followed after delivery. Samples were collected at 12 weeks post partum. Thiamine diphosphate (TDP) in whole blood and thiamine in breast-milk of 636 lactating women were measured. Thiamine in breast-milk consisted of thiamine monophosphate (TMP) in addition to thiamine, with a mean TMP to total thiamine ratio of 63%. Mean whole blood TDP (130 nmol/L) and total thiamine in breast-milk (755 nmol/L) were within the upper range reported for well-nourished women. The prevalence of women with low whole blood TDP (<65 nmol/L) was 5% and with deficient breast-milk total thiamine (<300 nmol/L) was 4%. Whole blood TDP predicted both breast-milk thiamine and TMP (R2 = 0.36 and 0.10, p<0.001). A ratio of TMP to total thiamine ≥63% was associated with a 7.5 and 4-fold higher risk of low whole blood TDP and deficient total breast-milk thiamine, respectively. Routine provision of daily 100 mg of thiamine mononitrate post-partum compared to the previous weekly 10 mg of thiamine hydrochloride resulted in significantly higher total thiamine in breast-milk.
Conclusions/Significance
Thiamine supplementation for lactating women in Maela refugee camp is effective and should be continued. TMP and its ratio to total thiamine in breast-milk, reported for the first time in this study, provided useful information on thiamine status and should be included in future studies of breast-milk thiamine.
doi:10.1371/journal.pone.0036280
PMCID: PMC3387174  PMID: 22768031
2.  Pharmacokinetic investigation of dose proportionality with a 24-hour controlled-release formulation of hydromorphone 
Background
The purpose of this study was investigate the dose proportionality of a novel, once-daily, controlled-release formulation of hydromorphone that utilizes the OROS® Push-Pull™ osmotic pump technology.
Methods
In an open-label, four-way, crossover study, 32 healthy volunteers were randomized to receive a single dose of OROS® hydromorphone 8, 16, 32, and 64 mg, with a 7-day washout period between treatments. Opioid antagonism was provided by three or four doses of naltrexone 50 mg, given at 12-hour intervals pre- and post-OROS® hydromorphone dosing. Plasma samples for pharmacokinetic analysis were collected pre-dose and at regular intervals up to 48 hours post-dose (72 hours for the 64-mg dose), and were assayed for hydromorphone concentration to determine peak plasma concentration (Cmax), time at which peak plasma concentration was observed (Tmax), terminal half-life (t1/2), and area under the concentration-time curve for zero to time t (AUC0-t) and zero to infinity (AUC0–∞). An analysis of variance (ANOVA) model on untransformed and dose-normalized data for AUC0-t, AUC0–∞, and Cmax was used to establish dose linearity and proportionality.
Results
The study was completed by 31 of 32 subjects. Median Tmax (12.0–16.0 hours) and mean t1/2 (10.6–11.0 hours) were found to be independent of dose. Regression analyses of Cmax, AUC0–48, and AUC0–∞ by dose indicated that the relationship was linear (slope, P ≤ 0.05) and that the intercept did not differ significantly from zero (P > 0.05). Similar analyses with dose-normalized parameters also indicated that the slope did not differ significantly from zero (P > 0.05).
Conclusion
The pharmacokinetics of OROS® hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses.
Trial Registration
Clinical Trials.gov NCT00398957
doi:10.1186/1472-6904-7-3
PMCID: PMC1808051  PMID: 17270058
3.  Effect of exenatide on the pharmacokinetics of a combination oral contraceptive in healthy women: an open-label, randomised, crossover trial 
Background
Consistent with its effect on gastric emptying, exenatide, an injectable treatment for type 2 diabetes, may slow the absorption rate of concomitantly administered oral drugs resulting in a decrease in maximum concentration (Cmax). This study evaluated the drug interaction potential of exenatide when administered adjunctively with oral contraceptives, given their potential concomitant use.
Methods
This trial evaluated the effect of exenatide co-administration on single- and multiple-dose pharmacokinetics of a combination oral contraceptive (ethinyl estradiol [EE] 30 μg, levonorgestrel [LV] 150 μg [Microgynon 30®]). Thirty-two healthy female subjects participated in an open-label, randomised, crossover trial with 3 treatment periods (oral contraceptive alone, 1 hour before exenatide, 30 minutes after exenatide). Subjects received a single dose of oral contraceptive on Day 8 of each period and QD doses on Days 10 through 28. During treatment periods of concomitant usage, exenatide was administered subcutaneously prior to morning and evening meals at 5 μg BID from Days 1 through 4 and at 10 μg BID from Days 5 through 22. Single- (Day 8) and multiple-dose (Day 22) pharmacokinetic profiles were assessed for each treatment period.
Results
Exenatide did not alter the bioavailability nor decrease daily trough concentrations for either oral contraceptive component. No substantive changes in oral contraceptive pharmacokinetics occurred when oral contraceptive was administered 1 hour before exenatide. Single-dose oral contraceptive administration 30 minutes after exenatide resulted in mean (90% CI) Cmax reductions of 46% (42-51%) and 41% (35-47%) for EE and LV, respectively. Repeated daily oral contraceptive administration 30 minutes after exenatide resulted in Cmax reductions of 45% (40-50%) and 27% (21-33%) for EE and LV, respectively. Peak oral contraceptive concentrations were delayed approximately 3 to 4 hours. Mild-to-moderate nausea and vomiting were the most common adverse events observed during the trial.
Conclusions
The observed reduction in Cmax is likely of limited importance given the unaltered oral contraceptive bioavailability and trough concentrations; however, for oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before exenatide injection.
Trial registration
ClinicalTrials.gov: NCT00254800.
doi:10.1186/1472-6904-12-8
PMCID: PMC3378442  PMID: 22429273
exenatide twice daily; pharmacokinetics; oral contraceptive
4.  Safety and pharmacokinetics of 5-chloro-2',3'-dideoxy-3'-fluorouridine (935U83) following oral administration of escalating single doses in human immunodeficiency virus-infected adults. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2842-2847.
5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83) is a nucleoside analog reverse transcriptase inhibitor that has demonstrated selective anti-human immunodeficiency virus (HIV) activity in vitro and favorable safety profiles in monkeys and mice. A phase I study was conducted to evaluate the safety and pharmacokinetics of six escalating single oral doses of 935U83 in 12 HIV-infected adults. The effect of a high-fat meal on the oral bioavailability of 935U83 was also assessed. The volunteers enrolled had CD4+ cell counts ranging from < 50 to 753 cells per mm3 (median, 198). In the dose range of 100 to 1,500 mg 935U83 was well tolerated by all subjects with no drug-related adverse events reported. No significant clinical or laboratory abnormalities were observed throughout the study. 935U83 was rapidly and well absorbed following oral administration with peak plasma concentrations (Cmax) occurring at 0.8 to 1.3 h postdosing. Mean Cmax and AUC0-infinity values of 935U83 were nearly dose proportional in the 100- to 1,500-mg dose range (from 2.4 to 30 micrograms/ml and from 3.4 to 59 h.micrograms/ml, respectively). Elimination of 935U83 from the plasma was rapid, with an apparent half-life of 1.3 to 1.7 h which was independent of the dose level. Administration of 935U83 with a high-fat meal decreased the rate of 935U83 absorption (mean Cmax decreased by approximately 50% and mean time to Cmax increased by approximately 1 h) but did not affect the extent of oral bioavailability (AUC0-infinity) of 935U83. The 5'-O-glucuronide conjugate was the principal metabolite of 935U83 and was present in the plasma of all volunteers at concentrations lower than 935U83. The molar AUC0-infinity ratio (935U83 glucuronide to the parent compound) was similar across all dose levels (mean, 21 to 27%). At least 60% of the 935U83 dose was absorbed, and approximately an equal percentage of the dose (approximately 30%) was excreted as unchanged 935U83 and as 935U83 glucuronide. Systemic exposure to 935U83 at levels exceeding its average in vitro antiretroviral 50% inhibitory concentration (approximately 0.5 microgram/ml or 1.8 microM) can be achieved after a single oral dose.
PMCID: PMC163633  PMID: 9124852
5.  Pharmacokinetics and bioavailability of single dose ibuprofen and pseudoephedrine alone or in combination: a randomized three-period, cross-over trial in healthy Indian volunteers 
Objective: To compare the bioavailability of single dose ibuprofen 200 mg and pseudoephedrine hydrochloride 30 mg administered alone or in combination as an oral suspension.
Methods: This was a single-center, randomized, single-dose, open-label, 3-period, crossover study. After an overnight fast (≥10 h), 18 healthy male subjects received either ibuprofen 200 mg (reference-A), pseudoephedrine 30 mg (reference-B) or the combination (test-C) as a suspension, on 3 separate visits, with blood sampling up to 36-h post-dose. The primary pharmacokinetic parameters, maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) from time zero to last measurable concentration (AUC0−t) and extrapolated to infinity (AUC0−∞) were compared by an analysis of variance using log-transformed data. Bioequivalence was concluded if the 90% confidence intervals (CIs) of the adjusted geometric mean (gMean) ratios for Cmax and AUC were within the predetermined range of 80–125%, in accordance with regulatory requirements.
Results: For the test formulation, the ibuprofen gMean Cmax was 17.0 μg/mL (vs. 18.1 μg/mL for reference-A), AUC0−t was 57.1 (vs. 60.0 μg·h/mL), and AUC0−∞ was 59.9 μg·h/mL (vs. 63.1 μg·h/mL). The 90% CIs for the ratio (test/reference-A) were 81.0–108.1% for Cmax, 91.5–98.4% for AUC0−t and 91.6–97.9% for AUC0−∞. For pseudoephedrine, the gMean Cmax for the test formulation was 97.2 ng/mL (vs. 98.5 ng/mL for reference-B), AUC0−t was 878.4 (vs. 842.8 ng·h/mL) and AUC0−∞ was 907.8 ng·h/mL (vs. 868.3 ng·h/mL). The 90% CIs for the ratio (test/reference-B) were 92.4–106.9% for Cmax, 97.7–111.0% for AUC0−t and 97.9–111.3% for AUC0−∞. All treatments were well tolerated.
Conclusion: This oral suspension containing ibuprofen and pseudoephedrine combined in a new formulation met the regulatory criterion for bioequivalence compared with oral suspensions containing the individual components.
doi:10.3389/fphar.2014.00098
PMCID: PMC4023067  PMID: 24847268
bioequivalence; ibuprofen; NSAIDs; pseudoephedrine; pharmacokinetics
6.  Effect of a High-Calorie, High-Fat Meal on the Bioavailability and Pharmacokinetics of PA-824 in Healthy Adult Subjects 
Antimicrobial Agents and Chemotherapy  2013;57(11):5516-5520.
PA-824 is a novel nitroimidazo-oxazine being developed as an antituberculosis agent. Two randomized studies evaluated the pharmacokinetics and safety of a single oral dose of PA-824 administered to healthy adult subjects 30 min after a high-calorie, high-fat meal (fed state) versus after a minimum 10-h fast (fasted state). A total of 48 subjects were dosed in the two studies in a randomized crossover design with PA-824 at dose levels of 50, 200, or 1,000 mg in the fed state or fasted state. After the administration of PA-824, the geometric mean ratios of Cmax and AUC0–∞ revealed an increase in exposure with the addition of a high-calorie, high-fat meal compared to the fasted state by 140 and 145% at 50 mg, 176 and 188% at 200 mg, and 450 and 473% at 50, 200, and 1,000 mg, respectively. The median Tmax in the fed state was 4 h for the 50-mg dose and 5 h for the 200- and 1,000-mg doses. In the fasted state, the median Tmax was 4 h for the 50- and 200-mg doses and 6.5 h for the 1,000-mg dose. All doses were well tolerated, and no serious adverse events occurred in either study. (This study has been registered at ClinicalTrials.gov under registration numbers NCT01828827 and NCT01830439.)
doi:10.1128/AAC.00798-13
PMCID: PMC3811266  PMID: 23979737
7.  Pharmacokinetic Profile of Lesogaberan (AZD3355) in Healthy Subjects 
Drugs in R&d  2012;11(1):77-83.
Objective: The aim of this study was to evaluate the pharmacokinetic profile of lesogaberan in healthy subjects after single oral and intravenous administration of 14C-labeled lesogaberan and non-14C-labeled lesogaberan.
Study Design: This was an open-label, single-center, randomized, two-way crossover, phase I study.
Participants: Ten healthy male subjects took part in the study.
Intervention: Volunteers were randomized to receive a single dose of either orally dosed (100 mg) or intravenously infused (20 mg) non-14C-labeled lesogaberan, and then orally (100 mg) or intravenously (20 mg) administered 14C-labeled lesogaberan in a crossover design. Treatment periods were separated by a washout period of at least 7 days.
Main Outcome Measures Analyses of the rate and route of excretion, dose recovery, area under the plasma concentration versus time curve (AUC), AUC to the last quantifiable concentration, maximal plasma concentration (Cmax), time to Cmax, the apparent elimination half-life, bioavailability, total clearance, renal clearance, fraction of the bioavailable dose excreted unchanged in the urine, cumulative amount of drug excreted unchanged in urine, and the apparent volume of distribution at steady state of lesogaberan.
Results: Lesogaberan was rapidly and extensively absorbed from the gastrointestinal tract and Cmax was achieved within 1–2 hours of oral dosing. The terminal half-life of lesogaberan was between 11 and 13 hours. Renal clearance accounted for approximately 22% of total body clearance. Based on the recovery of administered radioactivity, approximately 84% of the dose was excreted into the urine either as the parent compound or as water-soluble metabolite(s). There were no safety concerns raised during the study.
Conclusion: Orally administered lesogaberan is rapidly absorbed with high bioavailability and the majority of the dose is excreted by the kidneys either as the parent compound or as metabolites. The major elimination pathway for lesogaberan in man is metabolism.
doi:10.2165/11590310-000000000-00000
PMCID: PMC3585951  PMID: 21410297
8.  Pharmacokinetic Profile of Lesogaberan (AZD3355) in Healthy Subjects 
Drugs in R&D  2012;11(1):77-83.
Objective: The aim of this study was to evaluate the pharmacokinetic profile of lesogaberan in healthy subjects after single oral and intravenous administration of 14C-labeled lesogaberan and non-14C-labeled lesogaberan.
Study Design: This was an open-label, single-center, randomized, two-way crossover, phase I study.
Participants: Ten healthy male subjects took part in the study.
Intervention: Volunteers were randomized to receive a single dose of either orally dosed (100 mg) or intravenously infused (20 mg) non-14C-labeled lesogaberan, and then orally (100 mg) or intravenously (20 mg) administered 14C-labeled lesogaberan in a crossover design. Treatment periods were separated by a washout period of at least 7 days.
Main Outcome Measures Analyses of the rate and route of excretion, dose recovery, area under the plasma concentration versus time curve (AUC), AUC to the last quantifiable concentration, maximal plasma concentration (Cmax), time to Cmax, the apparent elimination half-life, bioavailability, total clearance, renal clearance, fraction of the bioavailable dose excreted unchanged in the urine, cumulative amount of drug excreted unchanged in urine, and the apparent volume of distribution at steady state of lesogaberan.
Results: Lesogaberan was rapidly and extensively absorbed from the gastrointestinal tract and Cmax was achieved within 1–2 hours of oral dosing. The terminal half-life of lesogaberan was between 11 and 13 hours. Renal clearance accounted for approximately 22% of total body clearance. Based on the recovery of administered radioactivity, approximately 84% of the dose was excreted into the urine either as the parent compound or as water-soluble metabolite(s). There were no safety concerns raised during the study.
Conclusion: Orally administered lesogaberan is rapidly absorbed with high bioavailability and the majority of the dose is excreted by the kidneys either as the parent compound or as metabolites. The major elimination pathway for lesogaberan in man is metabolism.
doi:10.2165/11590310-000000000-00000
PMCID: PMC3585951  PMID: 21410297
9.  Double-Blind Evaluation of the Safety and Pharmacokinetics of Multiple Oral Once-Daily 750-Milligram and 1-Gram Doses of Levofloxacin in Healthy Volunteers 
The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (Cmax) values were generally attained within 2 h postdose. The mean values of Cmax and area under the concentration-time curve from 0 to 24 h (AUC0–24) following a single 750-mg dose were 7.1 μg/ml and 71.3 μg · h/ml, respectively, compared to 8.6 μg/ml and 90.7 μg · h/ml, respectively, at steady state. Following the single 1-g dose, mean Cmax and AUC0–24 values were 8.9 μg/ml and 95.4 μg · h/ml, respectively; corresponding values at steady state were 11.8 μg/ml and 118 μg · h/ml. These Cmax and AUC0–24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life (t1/2), and renal clearance (CLR) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, Vss/F, t1/2, and CLR following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.
PMCID: PMC105560  PMID: 9559801
10.  Phase I Safety and Pharmacokinetic Trials of 1263W94, a Novel Oral Anti-Human Cytomegalovirus Agent, in Healthy and Human Immunodeficiency Virus-Infected Subjects 
1263W94 [maribavir; 5,6-dichloro-2-(isopropylamino)-1, β-l-ribofuranosyl-1-H-benzimidazole], a novel benzimidazole compound, has been demonstrated to potently and selectively inhibit human cytomegalovirus replication in vitro and to have favorable safety profiles in animal species. Two phase I trials evaluated the safety and pharmacokinetics of escalating single doses of 1263W94 in 13 healthy subjects (dose, 50 to 1,600 mg) and 17 human immunodeficiency virus (HIV)-infected subjects (dose, 100 to 1,600 mg). No severe safety concerns were observed in the evaluation of adverse events, vital signs, electrocardiograms, and clinical laboratory tests following administration of a single dose of 1263W94. The most frequently reported adverse events in both populations were taste disturbance (80%) and headache (53%). 1263W94 was rapidly absorbed following oral administration, with peak concentrations in plasma (Cmax) occurring 1 to 3 h after dosing. The increases in the Cmax of 1263W94 and the area under the concentration-time curve from time zero to infinity (AUC0-∞) for 1263W94 were dose dependent; Cmax increased slightly less than proportionally to the dose, and AUC0-∞ increased slightly more than proportionally to the dose. 1263W94 was rapidly eliminated, with a mean half-life in plasma of 3 to 5 h; the half-life was independent of the dose level. Less than 2% of the 1263W94 dose administered was eliminated unchanged in urine. The principal metabolite of 1263W94 was 4469W94 (which is derived by N-dealkylation of 1263W94 via CYP3A4), which accounted for 30 to 40% of the dose in urine. Greater than 98% of the 1263W94 in plasma is bound to proteins, and the extent of binding appears to be constant over the dose range of 200 to 1,600 mg. In the trial with HIV-infected subjects, consumption of a high-fat meal decreased the 1263W94 AUC0-∞ and Cmax in plasma by ∼30%.
doi:10.1128/AAC.47.4.1334-1342.2003
PMCID: PMC152490  PMID: 12654667
11.  Improved Pharmacokinetics of Sumatriptan With Breath Powered™ Nasal Delivery of Sumatriptan Powder 
Headache  2013;53(8):1323-1333.
Objectives.—
The purpose of this study was to directly compare the pharmacokinetic (PK) profile of 22-mg sumatriptan powder delivered intranasally with a novel Breath Powered™ device (11 mg in each nostril) vs a 20-mg sumatriptan liquid nasal spray, a 100-mg oral tablet, and a 6-mg subcutaneous injection.
Background.—
A prior PK study found that low doses of sumatriptan powder delivered intranasally with a Breath Powered device were efficiently and rapidly absorbed. An early phase clinical trial with the same device and doses found excellent tolerability with high response rates and rapid onset of pain relief, approaching the benefits of injection despite significantly lower predicted drug levels.
Methods.—
An open-label, cross-over, comparative bioavailability study was conducted in 20 healthy subjects at a single center in the USA. Following randomization, fasted subjects received a single dose of each of the 4 treatments separated by a 7-day washout. Blood samples were taken pre-dose and serially over 14 hours post-dose for PK analysis.
Results.—
Quantitative measurement of residuals in used Breath Powered devices demonstrated that the devices delivered 8 ± 0.9 mg (mean ± standard deviation) of sumatriptan powder in each nostril (total dose 16 mg). Although the extent of systemic exposure over 14 hours was similar following Breath Powered delivery of 16-mg sumatriptan powder and 20-mg liquid nasal spray (area under the curve [AUC]0-∞ 64.9 ng*hour/mL vs 61.1 ng*hour/mL), sumatriptan powder, despite a 20% lower dose, produced 27% higher peak exposure (Cmax 20.8 ng/mL vs 16.4 ng/mL) and 61% higher exposure in the first 30 minutes compared with the nasal spray (AUC0-30 minutes 5.8 ng*hour/mL vs 3.6 ng*hour/mL). The magnitude of difference is larger on a per-milligram basis. The absorption profile following standard nasal spray demonstrated bimodal peaks, consistent with lower early followed by higher later absorptions. In contrast, the profile following Breath Powered delivery showed higher early and lower late absorptions. Relative to the 100-mg oral tablet (Cmax 70.2 ng/mL, AUC0-∞, 308.8 ng*hour/mL) and 6-mg injection (Cmax 111.6 ng/mL, AUC0-∞ 128.2 ng*hour/mL), the peak and overall exposure following Breath Powered intranasal delivery of sumatriptan powder was substantially lower.
Conclusions.—
Breath Powered intranasal delivery of sumatriptan powder is a more efficient form of drug delivery, producing a higher peak and earlier exposure with a lower delivered dose than nasal spray and faster absorption than either nasal spray or oral administration. It also produces a significantly lower peak and total systemic exposure than oral tablet or subcutaneous injection.
doi:10.1111/head.12167
PMCID: PMC4232272  PMID: 23992438
sumatriptan; migraine; bidirectional nasal delivery; Breath Powered nasal delivery; pharmacokinetics; bioavailability
12.  Effect of MMX® mesalamine coadministration on the pharmacokinetics of amoxicillin, ciprofloxacin XR, metronidazole, and sulfamethoxazole: results from four randomized clinical trials 
Background
MMX® mesalamine is a once daily oral 5-aminosalicylic acid formulation, effective in induction and maintenance of ulcerative colitis remission. Patients on long-term mesalamine maintenance may occasionally require concomitant antibiotic treatment for unrelated infections.
Aim
To evaluate the potential for pharmacokinetic interactions between MMX mesalamine and amoxicillin, ciprofloxacin extended release (XR), metronidazole, or sulfamethoxazole in four open-label, randomized, placebo-controlled, two-period crossover studies.
Methods
In all four studies, healthy adults received placebo once daily or MMX mesalamine 4.8 g once daily on days 1–4 in one of two treatment sequences. In studies 1 and 2, subjects also received a single dose of amoxicillin 500 mg (N=62) or ciprofloxacin XR 500 mg (N=30) on day 4. In studies 3 and 4, subjects received metronidazole 750 mg twice daily on days 1–3 and once on day 4 (N=30); or sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily on days 1–3 and once on day 4 (N=44).
Results
MMX mesalamine had no significant effects on systemic exposure to amoxicillin, ciprofloxacin, or metronidazole; the 90% confidence intervals (CIs) around the geometric mean ratios (antibiotic + MMX mesalamine: antibiotic + placebo) for maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) fell within the predefined equivalence range (0.80–1.25). Sulfamethoxazole exposure increased by a statistically significant amount when coadministered with MMX mesalamine; however, increased exposure (by 12% in Cmax at steady state; by 15% in AUC at steady state) was not considered clinically significant, as the 90% CIs for each point estimate fell entirely within the predefined equivalence range. Adverse events in all studies were generally mild.
Conclusion
MMX mesalamine may be coadministered with amoxicillin, ciprofloxacin, metronidazole, or sulfamethoxazole, without affecting pharmacokinetics or safety of these antibiotics.
ClinicalTrials.gov identifiers
NCT01442688, NCT01402947, NCT01418365, and NCT01469637.
doi:10.2147/DDDT.S55373
PMCID: PMC4029757  PMID: 24868146
ulcerative colitis; pharmacokinetics; safety
13.  Metabolite Parameters as an Appropriate Alternative Approach for Assessment of Bioequivalence of Two Verapamil Formulations 
A bioequivalence study of two verapamil formulations (generic verapamil tablets and Isoptin® tablets) was performed by comparing pharmacokinetic parameters of the parent drug and its major metabolite, norverapamil following a single dose administration of 80 mg verapamil hydrochloride in 22 healthy volunteers according to a randomized, two-period, crossover-design study. Moreover, the feasibility of proving bioequivalence of verapamil oral dosing form by means of norverapamil pharmacokinetic parameters was evaluated. Concentrations of verapamil and norverapamil were quantified in plasma using a validated high-performance liquid chromatography (HPLC) with fluorescence detection. The 90% CIs for the log-transformed ratios of verapamil Cmax (maximum plasma concentration) and AUC0–∞(area under the plasma concentration-versus-time curve from time zero to the infinity) were 73 to 101 and 80 to 103, respectively. Similarly, the corresponding ranges for norverapamil were 80-100 and 84-103, respectively. According to the parent drug data, the 90% confidence intervals around the geometric mean ratio of AUC happened to fit within preset bioequivalence limits of 80–125%, whereas those for Cmax did not. The 90% confidence intervals for both Cmax and AUC of norverapamil met preset bioequivalence limits. The AUC and Cmax of metabolite, when compared to parent drug, showed a much lower degree of variability and the 90% confidence intervals of the metabolite were therefore narrower than those of the parent drug. These observations indicate that bioequivalence studies using metabolite, norverapamil, could be a more suitable and preferable approach to assess bioequivalence of verapamil formulations due to its much lower variability and therefore lower number of volunteers that are required to conduct the study.
PMCID: PMC4157014  PMID: 25237334
Bioequivalence study; Pharmacokinetics; Verapamil; Norverapamil; High variability
14.  Tigecycline Does Not Prolong Corrected QT Intervals in Healthy Subjects 
We evaluated the effect of tigecycline (50-mg and 200-mg doses) on corrected QT (QTc) intervals and assessed safety and tolerability in a randomized, placebo-controlled, four-period crossover study of 48 (44 male) healthy volunteers aged 22 to 53 years. Fed subjects received tigecycline (50 mg or 200 mg) or placebo in a blinded fashion or an open-label oral dose of moxifloxacin (400 mg) after 1 liter of intravenous fluid. Serial electrocardiograms were recorded before, and for 96 h after, dosing. Blood samples for tigecycline pharmacokinetics were collected after each recording. QTc intervals were corrected using Fridericia's correction (QTcF). Pharmacokinetic parameters were calculated using noncompartmental methods with potential relationships examined using linear mixed-effects modeling. Adverse events were recorded. The upper limits of the 90% confidence interval for the mean difference between both tigecycline doses and placebo for all time-matched QTcF interval changes from baseline were <5 ms. The tigecycline concentrations initially declined rapidly and then more slowly. In the group given 50 mg of tigecycline, the pharmacokinetic parameters and means were as follows: maximum concentration of drug in serum (Cmax), 432 ng/ml; area under the concentration-time curve from time zero extrapolated to infinity (AUC0–∞), 2,366 ng · h/ml; clearance (CL), 21.1 liters/h; volume of distribution at steady state (Vss), 610 liters; and terminal half-life (t1/2), 22.1 h. Proportional or similar values were found for the group given 200 mg of tigecycline. Linear mixed-effects modeling failed to show an effect on QTcF values by tigecycline concentrations (P = 0.755). Tigecycline does not prolong the QTc interval in healthy subjects. This study has been registered at ClinicalTrials.gov under registration no. NCT01287793.
doi:10.1128/AAC.01576-12
PMCID: PMC3623319  PMID: 23403419
15.  Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study 
Background
The CC-chemokine receptor 4 (CCR4) is thought potentially to play a critical role in asthma pathogenesis due to its ability to recruit type 2 T-helper lymphocytes to the inflamed airways. Therefore, CCR4 provides an excellent target for anti-inflammatory therapy.
Methods
The safety, tolerability, pharmacokinetics and pharmacodynamics of the CCR4 antagonist GSK2239633, N-(3-((3-(5-chlorothiophene-2-sulfonamido)-4-methoxy-1H-indazol-1-yl)methyl)benzyl)-2-hydroxy-2-methylpropanamide, were examined in healthy males. Two studies were performed: 1) an open-label, study in which six subjects received a single intravenous infusion of [14C]-GSK2239633 100 μg (10 kBq) (NCT01086462), and 2) a randomised, double-blind, placebo-controlled, cross-over, ascending dose study in which 24 subjects received single oral doses of GSK2239633 150–1500 mg (NCT01371812).
Results
Following intravenous dosing, plasma GSK2239633 displayed rapid, bi-phasic distribution and slow terminal elimination (t½: 13.5 hours), suggesting that GSK2239633 was a low to moderate clearance drug. Following oral dosing, blood levels of GSK2239633 reached Cmax rapidly (median tmax: 1.0–1.5 hours). Estimated GSK2239633 bioavailability was low with a maximum value determined of only 16%. Food increased GSK2239633 systemic exposure (as assessed by AUC and Cmax). Increases in AUC and Cmax were less than dose proportional. Adverse events were reported by three subjects (50%) following intravenous administration, and by 19 subjects (79%) following oral administration; most (46/47; 98%) events were mild/moderate in intensity. GSK2239633 1500 mg inhibited thymus- and activation-regulated chemokine-induced (TARC) actin polymerisation reaching a mean CCR4 occupancy of 74%.
Conclusion
In conclusion, GSK2239633 was well-tolerated and capable of inhibiting TARC from activating the CCR4 receptor.
doi:10.1186/2050-6511-14-14
PMCID: PMC3599276  PMID: 23448278
GSK2239633; CCR4; Microdose; Healthy
16.  Safety and Pharmacokinetics of Amprenavir (141W94), a Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor, following Oral Administration of Single Doses to HIV-Infected Adults 
We conducted a double-blind, placebo-controlled, parallel, dose-escalation trial to evaluate the pharmacokinetics and safety of single, oral doses of amprenavir (141W94; formerly VX-478), a potent inhibitor of human immunodeficiency virus (HIV) type 1 protease, administered as hard gelatin capsules in 12 HIV-infected subjects. The doses of amprenavir evaluated were 150, 300, 600, 900, and 1,200 mg. Amprenavir was rapidly absorbed, with the time to maximum concentration occurring within 1 to 2 h after dosing. On the basis of power model analysis, the increase in the maximum concentration of amprenavir in plasma (Cmax) was less than dose proportional, and the increase in the area under the concentration-time curve from time zero to infinity (AUC0–∞) was greater than dose proportional; mean slopes (with 90% confidence intervals) were 1.25 (1.16 to 1.35) and 0.78 (0.78 to 0.86) for AUC0–∞ and Cmax, respectively. Amprenavir was eliminated slowly, with a terminal-phase half-life of 8 h. A second study was conducted to determine the bioavailability of the hard gelatin capsule relative to that of a subsequently developed soft gelatin capsule. The capsules were bioequivalent in terms of AUC0–∞ but not in terms of Cmax; geometric-least-squares means ratios (with 90% confidence intervals) were 1.03 (0.92 to 1.14) and 1.25 (1.03 to 1.53) for AUC0–∞ and Cmax, respectively. Administration of soft gelatin capsules of amprenavir with a high-fat breakfast resulted in a 14% decrease in the mean AUC0–∞ (from 9.58 to 8.26 μg · h/ml), which is not likely to be clinically significant. The most common adverse events related to amprenavir were headache, nausea, and hypesthesia. Amprenavir appears to be safe and well tolerated over the dose range of 150 to 1200 mg. On the basis of the present single-dose studies, amprenavir is an HIV protease inhibitor with favorable absorption and clearance pharmacokinetics that are only minimally affected by administration with food.
PMCID: PMC89344  PMID: 10390223
17.  First human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitus 
Background
Remogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium-dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans.
Methods
This double-blind, randomized, placebo-controlled, single-dose, dose-escalation, crossover study is the first human trial designed to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of RE. All subjects received single oral doses of either RE or placebo separated by approximately 2 week intervals. In Part A, 10 healthy subjects participated in 5 dosing periods where they received RE (20 mg, 50 mg, 150 mg, 500 mg, or 1000 mg) or placebo (4:1 active to placebo ratio per treatment period). In Part B, 6 subjects with type 2 diabetes mellitus (T2DM) participated in 3 dose periods where they received RE (50 mg and 500 mg) or placebo (2:1 active to placebo per treatment period). The study protocol was registered with the NIH clinical trials data base with identifier NCT01571661.
Results
RE was generally well-tolerated; there were no serious adverse events. In both populations, RE was rapidly absorbed and converted to remogliflozin (time to maximum plasma concentration [Cmax;Tmax] approximately 1 h). Generally, exposure to remogliflozin was proportional to the administered dose. RE was rapidly eliminated (mean T½ of ~25 min; mean plasma T½ for remogliflozin was 120 min) and was independent of dose. All subjects showed dose-dependent increases in 24-hour UGE, which plateaued at approximately 200 to 250 mmol glucose with RE doses ≥150 mg. In T2DM subjects, increased plasma glucose following OGTT was attenuated by RE in a drug-dependent fashion, but there were no clear trends in plasma insulin. There were no apparent effects of treatment on plasma or urine electrolytes.
Conclusions
The results support progression of RE as a potential treatment for T2DM.
Trial registration
ClinicalTrials.gov NCT01571661
doi:10.1186/2050-6511-14-26
PMCID: PMC3700763  PMID: 23668634
Remogliflozin etabonate; Sodium-dependent glucose transporter 2 inhibitor; Pharmacokinetics; Pharmacodynamics; Type 2 diabetes mellitus
18.  Bioequivalence of the 4-mg Oral Granules and Chewable Tablet Formulations of Montelukast 
Archives of Drug Information  2010;3(2):37-43.
Purpose
The primary objective of the studies was to demonstrate bioequivalence between the oral granules formulation and chewable tablet of montelukast in the fasted state. Effect of food on the pharmacokinetics of the oral granules was also evaluated.
Methods
The Formulation Biocomparison Study (Study 1) and the Final Market Image Study (Study 2) each used an open-label, randomized, 3-period crossover design where healthy adult subjects (N = 24 and 30, respectively) received montelukast as a single 4-mg dose of the oral granules formulation and a 4-mg chewable tablet fasted, and a single 4-mg dose of the oral granules formulation with food (on 2 teaspoons of applesauce [Study 1] or after consumption of a high-fat breakfast [Study 2]). The formulations were to be considered bioequivalent if the 90% confidence intervals (CIs) for geometric mean ratios (GMRs) (oral granules/chewable tablet) for the AUC0-∞ and Cmax of montelukast were within the prespecified comparability bounds of (0.80, 1.25). For the food-effect assessment in Study 1, comparability bounds were prespecified as (0.50, 2.00) only for the 90% CI of the GMR (oral granules fed/oral granules fasted) for the AUC0-∞ of montelukast; the 90% CI of the GMR for the Cmax of montelukast, however, also was computed. In Study 2, 90% CIs of the GMRs (oral granules fed/oral granules fasted) for the AUC0-∞ and Cmax of montelukast were computed; comparability bounds were not prespecified.
Results
Comparing the exposure of the formulations, the 90% CIs of the GMRs for AUC0-∞ and Cmax were within the prespecified bound of (0.80, 1.25). For AUC0-∞, the GMRs (90% CI) for Study 1 and Study 2 were 1.01 (0.92, 1.11) and 0.95 (0.91, 0.99), respectively. For Cmax, respective values were 0.99 (0.86, 1.13) and 0.92 (0.84, 1.01). When the oral granules formulation was administered with food, 90% CIs of the GMRs for both AUC0-∞ and Cmax in both studies were contained within the interval of (0.50, 2.00).
Conclusions
The 4-mg oral granules and 4-mg chewable tablet formulations of montelukast administered in the fasted state are bioequivalent. Single 4-mg doses of the oral granules formulation and the chewable tablet of montelukast are generally well tolerated.
doi:10.1111/j.1753-5174.2010.00029.x
PMCID: PMC2913109  PMID: 20686624
Montelukast; Pediatric Formulations; Bioequivalence; Pharmacokinetics
19.  Single- and multiple-dose pharmacokinetics of genistein capsules in healthy chinese subjects: A phase I, randomized, open-label study 
Background: Genistein capsules are currently being developed to treat osteoporosis in China. Genistein is extracted from the fruit of Sophora japonica Leguminosae.
Objective: The objective of this study was to assess the pharmacokinetics of genistein capsules after single and multiple oral doses in healthy Chinese subjects.
Methods: This was a Phase I, randomized, open-label, single- and multiple- dose study in healthy Chinese adults (aged 19–40 years). In the single-dose study, subjects were randomly assigned in a 1:1:1 ratio to receive genistein 50, 100, or 300 mg (in 50-mg capsules). To assess the effect of food on the pharmacokinetics, subjects in the 50-mg group were equally randomized again into fasting and postprandial (genistein was administered after a high-fat breakfast) groups according to a 2-way cross-over design. A separate equal-sized group of subjects were administered genistein 50 mg on day 1 (single dose), received no treatment on days 2 and 3, and were administered genistein 50 mg QD for 6 days (days 4–9) to obtain a multiple-dose pharmacokinetic profile. Because genistein is converted so rapidly and completely to glucuronidated genistein after administration, plasma concentrations of glucuronidated genistein were determined using a validated high-performance liquid chromatography/ tandem mass spectrometry method. Drug tolerability was assessed by monitoring adverse events (AEs) and laboratory parameters.
Results: The study enrolled 40 healthy subjects (24 men, 16 women; 10 each in the 50-, 100-, and 300-mg single-dose groups and 10 in the multiple-dose group). Three subjects voluntarily withdrew (2 in the 100-mg group and 1 in the 300-mg group) before study drug administration. Thirty-seven subjects (24 men, 13 women) completed the study and were included in the analysis. The mean (SD) values of the single-dose genistein 50-, 100-, and 300-mg groups were as follows: Tmax, 6.0 (2.4), 7.4 (2.4), and 5.6 (1.2) hours, respectively; tl/2, 13.0 (4.0), 12.6 (5.8), and 9.4 (1.1) hours; AUC0−t, 3344 (1635), 8389 (5164), and 9361 (2428) ng/mL · h−1; and Cmax , 218.7 (68.6), 435.7 (202.1), and 553.4 (152.8) ng/mL. The plasma glucuronidated genistein concentrations were directly proportional to the administered dose over the range of 50 to 100 mg and increased nonproportionately with the 300-mg dose. No statistically significant differences in pharmacokinetic parameters were found in the fasting group compared with the postprandial group. In the multiple-dose group, the mean (SD) steady-state pharmacokinetic parameters on day 9 were similar to those following a single dose of genistein on day 1 (Tmax, 6.0 [1.0] vs 5.9 [1.5] hours, respectively; tl/2, 9.5 [1.5] vs 9.1 [1.5] hours; AUC0−t, 2830 [1541] vs 2078 [1308] ng/mL · h−1; Cmax, 203.1 [130.9] vs 168.4 [105.7] ng/mL). All AEs were assessed as mild or moderate and resolved without treatment, with the exception of elevated alanine aminotransferase and aspartate aminotransferase activities in one subject that resolved with treatment.
Conclusions: The pharmacokinetics of glucuronidated genistein appeared to fit the linear-dose range of genistein 50 to 100 mg, but not the 300-mg dose in these healthy Chinese volunteers. Food consumption did not significantly affect the pharmacokinetic properties. No significant differences were observed in the pharmacokinetic parameters after multiple doses of genistein compared with a single dose, suggesting that the drug did not accumulate after multiple doses.
doi:10.1016/j.curtheres.2008.08.006
PMCID: PMC3969939  PMID: 24692809
pharmacokinetics; genistein capsule; single dose; multiple dose; healthy Chinese subject
20.  Effect of Food on the Pharmacokinetic Profile of Etamicastat (BIA 5-453) 
Drugs in R&d  2012;11(2):127-136.
Background: Etamicastat is a novel, potent, and reversible peripheral dopamine-β-hydroxylase inhibitor that has been administered orally at doses up to 600mg once daily for 10 days to male healthy volunteers and appears to be well tolerated.
Objective: The aim of this study was to investigate the effect of food on the pharmacokinetics of etamicastat.
Material and Methods: A single-center, open-label, randomized, two-way crossover study in 12 healthy male subjects was performed. Subjects were administered a single dose of etamicastat 200mg following either a standard high-fat and high-calorie content meal (test) or 10 hours of fasting (reference). The statistical method for testing the effect of food on the pharmacokinetic parameters of interest was based upon the 90% confidence interval (CI) for the test/reference geometric mean ratio (GMR). The parameters of interest were maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration (AUClast), and AUC from time zero to infinity (AUC∞). Bioequivalence was assumed when the 90% CI fell within the recommended acceptance interval (80, 125).
Results: Etamicastat Cmax, AUClast, and AUC∞ were 229 ng/mL, 1856 • h/mL, and 2238 ng • h/mL, respectively, following etamicastat in the fasting, and 166 ng/mL, 1737 ng • h/mL, and 2119 ng • h/mL, respectively, following etamicastat in the fed condition. Etamicastat test/reference GMR was 72.27% (90% CI 64.98, 80.38) for Cmax, 93.59% (90% CI 89.28, 98.11) for AUClast, and 96.47% (90% CI 91.67, 101.53) for AUC∞. Time to Cmax was prolonged by the presence of food (p < 0.001). The Cmax, AUClast, and AUC∞ values of the inactive metabolite BIA 5-961 were 275 ng/mL, 1827 ng • h/mL, and 2009 ng • h/mL, respectively, in the fasting, and 172 ng/mL, 1450 ng • h/mL, and 1677 ng • h/mL, respectively, in the fed condition. BIA 5-961 test/reference GMR was 62.42% (90% CI 56.77, 68.63) for Cmax, 79.41% (90% CI 56.77, 68.63) for AUClast, and 83.47% (90% CI 76.62, 90.93) for AUC∞. A total of six mild to moderate unspecific adverse events were reported by four subjects. There was no clinically significant abnormality in laboratory assessments.
Conclusion: Etamicastat was well tolerated. The Cmax of etamicastat decreased 28% following oral administration of etamicastat in the presence of food, while AUC remained within the pre-defined acceptance interval. The delay in absorption and decrease in peak exposure of etamicastat is not clinically significant, and therefore etamicastat could be administered without regard to meals.
doi:10.2165/11587080-000000000-00000
PMCID: PMC3585837  PMID: 21548660
21.  Effect of Food on the Pharmacokinetic Profile of Etamicastat (BIA 5-453) 
Drugs in R&D  2012;11(2):127-136.
Background: Etamicastat is a novel, potent, and reversible peripheral dopamine-β-hydroxylase inhibitor that has been administered orally at doses up to 600mg once daily for 10 days to male healthy volunteers and appears to be well tolerated.
Objective: The aim of this study was to investigate the effect of food on the pharmacokinetics of etamicastat.
Material and Methods: A single-center, open-label, randomized, two-way crossover study in 12 healthy male subjects was performed. Subjects were administered a single dose of etamicastat 200mg following either a standard high-fat and high-calorie content meal (test) or 10 hours of fasting (reference). The statistical method for testing the effect of food on the pharmacokinetic parameters of interest was based upon the 90% confidence interval (CI) for the test/reference geometric mean ratio (GMR). The parameters of interest were maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration (AUClast), and AUC from time zero to infinity (AUC∞). Bioequivalence was assumed when the 90% CI fell within the recommended acceptance interval (80, 125).
Results: Etamicastat Cmax, AUClast, and AUC∞ were 229 ng/mL, 1856 • h/mL, and 2238 ng • h/mL, respectively, following etamicastat in the fasting, and 166 ng/mL, 1737 ng • h/mL, and 2119 ng • h/mL, respectively, following etamicastat in the fed condition. Etamicastat test/reference GMR was 72.27% (90% CI 64.98, 80.38) for Cmax, 93.59% (90% CI 89.28, 98.11) for AUClast, and 96.47% (90% CI 91.67, 101.53) for AUC∞. Time to Cmax was prolonged by the presence of food (p < 0.001). The Cmax, AUClast, and AUC∞ values of the inactive metabolite BIA 5-961 were 275 ng/mL, 1827 ng • h/mL, and 2009 ng • h/mL, respectively, in the fasting, and 172 ng/mL, 1450 ng • h/mL, and 1677 ng • h/mL, respectively, in the fed condition. BIA 5-961 test/reference GMR was 62.42% (90% CI 56.77, 68.63) for Cmax, 79.41% (90% CI 56.77, 68.63) for AUClast, and 83.47% (90% CI 76.62, 90.93) for AUC∞. A total of six mild to moderate unspecific adverse events were reported by four subjects. There was no clinically significant abnormality in laboratory assessments.
Conclusion: Etamicastat was well tolerated. The Cmax of etamicastat decreased 28% following oral administration of etamicastat in the presence of food, while AUC remained within the pre-defined acceptance interval. The delay in absorption and decrease in peak exposure of etamicastat is not clinically significant, and therefore etamicastat could be administered without regard to meals.
doi:10.2165/11587080-000000000-00000
PMCID: PMC3585837  PMID: 21548660
22.  Metabolic Benefits of Six-month Thiamine Supplementation in Patients With and Without Diabetes Mellitus Type 2 
Thiamine deficiency has been documented to be prevalent in patients with diabetes mellitus, and correction of thiamine deficiency in this population may provide beneficial effects in several cardiometabolic parameters, including prevention of impending complications secondary to chronic hyperglycemia. In this interventional study, we aim to determine whether thiamine supplementation is associated with cardiometabolic improvements in patients with diabetes mellitus type 2 (DMT2). A total of 86 subjects (60 DMT2 and 26 age- and BMI-matched controls) were included and were given thiamine supplements (100 mg/day) for six months. Anthropometrics and metabolic profiles were measured routinely. Serum thiamine and its derivatives were measured using high performance liquid chromatography. In all groups, there was a significant decrease in total cholesterol after three months (p = 0.03) as well as in HDL cholesterol after six months of thiamine supplementation (p = 0.009). Significant improvements were also observed in the mean serum levels of creatinine (p = 0.001), as well as thiamine and its derivatives in both serum and urinary levels across follow-up visits (p-values 0.002 and <0.001, respectively). In the DMT2 group, improvements were observed in lipid profile (mean serum LDL and total cholesterol with p-values 0.008 and 0.006, respectively), serum thiamine (p < 0.001), TMP (p < 0.001), TDP (p < 0.001), urinary thiamine (p < 0.001) and serum creatinine (p < 0.001). Thiamine supplementation is a promising adjuvant therapy for patients with DMT2. Longer clinical trials are needed to determine its protective effect in DMT2 complications.
doi:10.4137/CMED.S13573
PMCID: PMC3921172  PMID: 24550684
thiamine; diabetes mellitus type 2; Saudi; supplements
23.  Comparative Bioavailability and Tolerability of a Single 2-mg Dose of 2 Repaglinide Tablet Formulations in Fasting, Healthy Chinese Male Volunteers: An Open-Label, Randomized-Sequence, 2-Period Crossover Study☆ 
Background
Repaglinide, an oral insulin secretagogue, was the first meglitinide analogue to be approved for use in patients with type 2 diabetes mellitus.
Objective
In our study, the bioavailability and tolerability of the proposed generic formulation with the established reference formulation of repaglinide 2 mg were compared in a fasting, healthy Chinese male population.
Methods
This 2-week, open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in 22 healthy native Han Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 2-mg dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. After an overnight fast, subjects received a single oral dose of repaglinide (2 mg). Blood samples were drawn at predetermined time points (0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, and 6.0 hours). All plasma concentrations of repaglinide were measured by LC-MS/MS. The observed Cmax, Tmax, t1/2, and AUC were assessed. The formulations were to be considered bioequivalent if the ln-transformed ratios of Cmax and AUC were within the predetermined bioequivalence range of 80% to 125% established by the State Food and Drug Administration of the People’s Republic of China. Tolerability was assessed throughout the study via subject interview, vital signs, and blood sampling.
Results
The mean (SD) age of the subjects was 24.2 (2.3) years; their mean (SD) weight was 62.6 (5.8) kg, their mean (SD) height was 172 (5.7) cm, and their mean (SD) body mass index was 21.0 (1.1). The mean (SD) Cmax for repaglinide with the test and reference formulations were 20.0 (5.1) and 18.7 (8.7) ng/mL. The AUC0–t for the test formulation was 46.3 (15.1) and AUC0–∞ was 47.9 (16.5) ng•h/mL. With the reference formulation, the corresponding values were 46.4 (26.1) and 49.0 (31.3) ng•h/mL. The mean (SD) Tmax values with the test and reference formulations were 1.2 (0.7) hours and 1.5 (0.8) hours and the mean (SD) values t1/2 values were 1.0 (0.3), and 0.9 (0.3) hours, respectively. The ln-transformed ratios of Cmax, AUC0–t, and AUC0–∞ were 113.6:1, 105.6:1, and 104.7:1. The corresponding 90% CIs were 99.8 to 129.2, 93.4 to 119.5, and 91.8 to 119.5, respectively.
Conclusions
This single-dose study found that the test and reference formulations of repaglinide met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. Both formulations appeared to be well tolerated. ClinicalTrials.gov identifier: 2012L01684.
doi:10.1016/j.curtheres.2013.08.001
PMCID: PMC3898188  PMID: 24465043
bioequivalence; pharmacokinetics; repaglinide; tolerability
24.  Pharmacokinetic profile of a 24-hour controlled-release OROS® formulation of hydromorphone in the presence and absence of food 
Background
The objective of this study was to compare the pharmacokinetic profile of a novel, once-daily, controlled-release formulation of hydromorphone (OROS® hydromorphone) under fasting conditions with that immediately after a high-fat breakfast in healthy volunteers. The effect of the opioid antagonist naltrexone on fasting hydromorphone pharmacokinetics also was evaluated.
Methods
In an open-label, three-way, crossover study, 30 healthy volunteers were randomized to receive a single dose of 16 mg OROS® hydromorphone under fasting conditions, 16 mg OROS® hydromorphone under fed conditions, or 16 mg OROS® hydromorphone under fasting conditions with a naltrexone 50-mg block. Plasma samples taken pre-dose and at regular intervals up to 48 hours post-dose were assayed for hydromorphone concentrations. Analysis of variance was performed on log-transformed data; for mean ratios of 0.8 to 1.2 (20%), differences were considered minimal. Bioequivalence was reached if 90% confidence intervals (CI) of treatment mean ratios were between 80% and 125%.
Results
The mean geometric ratios of the fed and fasting treatment groups for maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-t; AUC0-∞) were within 20%. Confidence intervals were within 80% to 125% for AUC0-t and AUC0-∞ but were slightly higher for Cmax (105.9% and 133.3%, respectively). With naltrexone block, the hydromorphone Cmax increased by 39% and the terminal half-life decreased by 4.5 hours. There was no significant change in Tmax, AUC0-t or AUC0-∞.
Conclusion
Standard bioavailability measures show minimal effect of food on the bioavailability of hydromorphone from OROS® hydromorphone. Naltrexone co-administration results in a slight increase in the rate of absorption but not the extent of absorption.
Trial Registration
Clinical Trials.gov NCT00399295
doi:10.1186/1472-6904-7-2
PMCID: PMC1810515  PMID: 17270055
25.  Effects of food on the bioavailability of gepirone from extended-release tablets in humans: results of two open-label crossover studies☆ 
Background
The new antidepressant gepirone acts preferentially on 5-hydroxytryptamine type 1A (5-HT1A) receptors and functions as a 5-HT1A agonist. Placebo-controlled clinical studies have established that gepirone has a good safety profile and is effective for the treatment of depression. A previous study showed that administration of gepirone immediate release 15 minutes after a meal instead of during a fast increased the mean area under the plasma concentration–time curve (AUC) by 37%. Gepirone was reformulated into extended release (ER), which necessitated further exploration of the effects of food on bioavailability.
Objective
This article describes 2 studies of the pharmacokinetic properties of gepirone ER and 1 of its metabolites, 1(2-pyrimidinyl)-piperazine (1-PP), in healthy subjects. In study 1, we assessed the effects of food and the influence of time of food intake relative to dosing on the bioavailability of gepirone ER. The objective of study 2 was to confirm that gepirone ER has similar pharmacokinetic characteristics under fed and fasting conditions.
Methods
Two open-label, randomized, single-dose, crossover studies balanced for first-order residual effects were conducted to assess the bioavailability of gepirone from ER tablets. Healthy male subjects received a 20-mg oral dose of gepirone ER. In study 1, subjects took the gepirone ER dose after a 10-hour overnight fast or 1 hour before, 15 minutes after, or 2 hours after a standard high-fat meal. In study 2, subjects either took the gepirone ER dose after a 10-hour overnight fast and continued to fast for 4 more hours or took the gepirone ER dose 15 minutes after a standard high-fat meal.
Results
Twenty-eight men (mean [SD] age, 27.2 [6.6] years) participated in study 1, and 27 men (mean [SD] age, 31.8 [9.6] years) participated in study 2. In study 1, the mean (SD) maximum peak plasma concentration (Cmax) for gepirone ER was 69.2% higher (3.25 [1.71] vs 1.92 [0.96] ng/mL) (P≤0.05) and the AUC from time 0 to 30 hours for gepirone ER was 31.9% higher (39.3 [20.6] vs 29.8 [15.3] ng/mL·h) (P≤0.05) for the 15-minute postprandial dose than for the fasting dose, respectively. In study 2, the mean Cmax for gepirone was 62.0% higher (4.13 vs 2.55 ng/mL) and the mean AUC from time 0 to infinity for gepirone was 24% higher (38.71 vs 31.14 ng/mL·h) for the postprandial dose than for the fasting dose (P<0.05). All reported adverse effects were mild to moderate in intensity, and most (study 1) or all (study 2) occurred during the fasting state.
Conclusions
When administered with food, the bioavailability (AUC and Cmax) of gepirone ER was greater than during the fasting state, with the greatest bioavailability seen when the drug was taken 15 minutes after eating. Based on this pharmacokinetic analysis, it may be prudent to administer gepirone ER consistently, either always with or always without food.
doi:10.1016/j.curtheres.2003.09.012
PMCID: PMC4053051  PMID: 24944406
gepirone; bioavailability; 5-HT1A agonist; depression; anxiety

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