HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF.
CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF).
Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2–17] of therapy were 2145 ng/mL in plasma (IQR 1384–4423) and 13.9 ng/mL in CSF (IQR 4.1–21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026–0.0076; n = 69). The CSF/IC50 ratio was 26 (IQR 8–41) using the published IC50 for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC50 for wild-type HIV.
Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC50 in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.
CNS; pharmacology; non-nucleoside reverse transcriptase inhibitors
Candida infections are a leading cause of infectious disease-related death in infants supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK), thus standard fluconazole dosing in children on ECMO may result in suboptimal drug exposure. This study determined the PK of fluconazole in infants on ECMO.
Infants <120 days old received either intravenous fluconazole prophylaxis (25 mg/kg once a week) or treatment (12 mg/kg daily) while on ECMO. Paired plasma samples were collected pre- and post-oxygenator around doses 1 and 2 to calculate PK indices and describe oxygenator extraction. A 1-compartment model was fit to the data using non-linear regression. Surrogate pharmacodynamic targets for efficacy were evaluated.
Ten infants were enrolled. After dose 1 (n=9), the median clearance was 17 mL/kg/h, the median volume of distribution was 1.5 L/kg, and the median exposure in the first 24 hours (AUC0–24) was 322 h*mg/L. After multiple doses (n=7), the median clearance was 22 mL/kg/h, the median volume of distribution was 1.9 L/kg, and the AUC0–24 was 352 h*mg/L. After dose 1, 78% of infants achieved the prophylaxis target, while only 11% achieved the therapeutic target. Oxygenator extraction of fluconazole was minimal (−2.0%, standard deviation 15.0), and extraction was not correlated with age of the ECMO circuit (rho= − 0.05). There were no adverse events related to fluconazole.
Infants on ECMO had higher volume of distribution but similar clearance when compared with historical controls not on ECMO. In infants on ECMO, a fluconazole dose of 25 mg/kg weekly provides adequate exposure for prophylaxis against Candida infections. However, higher doses may be needed for treatment.
fluconazole; Candida; extracorporeal membrane oxygenation; pharmacokinetics; infants
Identification of HIV infection in exposed infants facilitates early therapy, which may limit viral reservoirs that maintain HIV infection under HAART.
The dynamics of the resting CD4+ T-cell latent HIV reservoir was determined over the first 2 years of life in 17 HIV-infected infants initiating lopinavir/ritonavir-based HAART at a median age of 8.1 weeks and achieving adequate suppression of plasma viral load by 24 weeks.
The resting CD4+ T-cell latent HIV reservoir was detected in 12 of 14 (86%) infants tested at 24 weeks of HAART [median frequency 1.88 infectious units per million (IUPM); range <0.22 to 81.7), and remained measurable (median IUPM =0.32; range < 0.22 to 3.25) in six of 10 (60%) children retested at 96 weeks. The reservoir declined, from 24 to 96 weeks of HAART, at an estimated mean rate of 0.028 log10 IUPM/month, corresponding to a half-life of 11 months (95% confidence interval 6–30 months]. A strong relationship was found between the frequency of latently infected CD4+T cells at 96 weeks of HAART and time to first undetectable plasma viral load (Spearman r =0.91, P <0.001).
Although the resting CD4+ T-cell latent reservoir remains detectable over the first 2 years of HAART in a substantial proportion of infants, its size is associated with time to first undetectable viral load. To minimize HIV reservoirs in infants, rapid curtailment of viremia may limit HIV reservoirs and should be a therapeutic goal of early HAART in infants.
early HAART; infants; latent reservoir dynamics
We describe an unintentional significant overdose of darunavir in a treatment-experienced adolescent with decreased darunavir susceptibility and prior treatment failure on darunavir therapy. Minimal toxicity and improved virologic suppression observed with an overdose have prompted consideration of the continued use of higher than recommended dose. Pharmacokinetic and pharmacodynamic evaluations justified the individualized use of high-dose darunavir, which resulted in virologic suppression, improved CD4 count and resolution of toxicity.
Darunavir; Adolescent; Pharmacokinetics; Safety; HIV
To evaluate the single dose pharmacokinetics of an intravenous dose of lorazepam in pediatric patients treated for status epilepticus (SE) or with a history of SE.
Ten hospitals in the Pediatric Emergency Care Applied Research Network (PECARN) enlisted patients 3 months to 17 years with convulsive SE (STATUS) or for a traditional PK study (ELECTIVE). Sparse sampling was used for STATUS and intensive sampling for ELECTIVE. Noncompartmental analyses were performed on ELECTIVE, and served to nest compartmental population PK analysis for both cohorts.
48 STATUS and 15 ELECTIVE patients were enrolled. Median age was 7 years, 2 months. The population PK parameters were: clearance 1.2 mL/min/kg, half-life 16.8 hours, volume of distribution 1.5 L/kg. Based on the PK model, a 0.1 mg/kg dose is expected to achieve concentrations of approximately 100 ng/mL and maintain concentrations above 30–50 ng/mL for 6–12 hours. A second dose of 0.05 mg/kg would achieve desired therapeutic serum levels for approximately 12 hours without excessive sedation. Age-dependent dosing is not necessary beyond using a maximum initial dose of 4 mg.
Lorazepam PK in convulsive status epilepticus is similar to previous PK measured in pediatric patients with cancer, except for longer half-life and similar to adult PK parameters except for increased clearance.
Tenofovir is a nucleotide HIV reverse transcriptase inhibitor whose chemical properties suggest that it may not penetrate into the central nervous system in therapeutic concentrations. The study objective was to determine tenofovir penetration into cerebrospinal fluid (CSF).
CHARTER is a multi-center, observational study to determine effects of antiretroviral therapy on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within an hour of each other from subjects taking tenofovir between October 2003 and March 2007. All samples were assayed by mass spectrometry with a detection limit of 0.9 ng/mL.
183 participants (age 44 ± 8 years; 83 ± 32 kg; 33 females; CSF protein 44 ± 16 mg/dL) had plasma and CSF samples drawn 12.2 ± 6.9 and 11 ± 7.8 hours post-dose respectively. Median plasma and CSF tenofovir concentrations were 96 ng/mL (IQR 47 – 153) and 5.5 ng/mL (IQR 2.7 – 11.3), respectively. Thirty-four of 231 (14.7%) plasma and 9/77 (11.7%) CSF samples were below detection. CSF/plasma concentration ratio from paired samples was 0.057 (IQR 0.03 – 0.1; n=38). Median CSF/wild-type IC50 ratio was 0.48 (IQR 0.24 – 0.98). Seventy-seven percent of CSF concentrations were below the tenofovir wild-type IC50. More subjects had detectable CSF HIV with lower (≤ 7 ng/mL) versus higher (> 7ng/mL) CSF tenofovir concentrations (29% vs. 9%; p=0.05).
Tenofovir concentrations in the CSF are only 5% of plasma concentrations, suggesting limited transfer into the CSF, and possibly active transport out of the CSF. CSF tenofovir concentrations may not effectively inhibit viral replication in the CSF.
tenofovir; CSF; pharmacokinetics
Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) used worldwide as part of combination antiretroviral therapy in infants and children to treat HIV infection. Dosing based on either weight or body surface area has been approved by the U.S. Food and Drug Administration (FDA) but can be difficult to implement in resource-limited settings. The World Health Organization (WHO) has developed simplified weight band dosing for NVP, but it has not been critically evaluated. NVP pharmacokinetic data were combined from eight pediatric clinical trials (Pediatric AIDS Clinical Trials Group [PACTG] studies 245, 356, 366, 377, 403, 1056, and 1069 and Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens [CHAPAS]) representing subjects from multiple continents and across the pediatric age continuum. A population pharmacokinetic model was developed to characterize developmental changes in NVP disposition, identify potential sources of NVP pharmacokinetic variability, and assess various pediatric dosing strategies and their impact on NVP exposure. Age, CYP2B6 genotype, and ritonavir were independent predictors of oral NVP clearance. The Triomune fixed-dose tablet was an independent predictor of bioavailability compared to the liquid and other tablet formulations. Monte Carlo simulations of the final model were used to assess WHO weight band dosing recommendations. The final pharmacokinetic model indicated that WHO weight band dosing is likely to result in a percentage of children with NVP exposure within the target range similar to that obtained with FDA dosing. Weight band dosing of NVP proposed by the WHO has the potential to provide a simple and effective dosing strategy for resource limited settings.
The impact of pregnancy on efavirenz pharmacokinetics is unknown.
International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving 600 mg efavirenz once daily as part of combination antiretroviral therapy. Intensive steady-state 24-hour blood sampling was performed during the third trimester and at 6–12 weeks postpartum. Maternal and umbilical cord blood samples were drawn at delivery. Pharmacokinetics targets were the estimated 10th percentile efavirenz AUC in non-pregnant historical controls (40.0 mcg.hr/mL) and a trough concentration of 1 mcg/mL.
Twenty five women were enrolled during the third trimester: median (range) age was 29.3 (18.9–42.9) years, weight 69.0 (40–130) kg, gestational age 32.9 (30.1–38.7) weeks. Median (range) efavirenz AUC0-24, Cmax and C24hour were 55.4 mcg.hr/mL (13.5–220.3), 5.4 mcg/mL (1.9–12.2) and 1.6 mcg/ml (0.23–8.13), respectively. Efavirenz AUC and Cmax did not differ during pregnancy and postpartum but C24hour was lower during the third trimester (1.6 vs. 2.1 mcg/mL, p=0.01). During the third trimester, 5 of 25 (20%) women had an efavirenz AUC below the target and 3 of 25 (12%) had a trough concentration below 1 mcg/mL. Efavirenz cord blood/maternal concentration ratio was 0.49 (0.37–0.74). All women had a HIV-1 RNA viral load less than 400 copies/mL at delivery and 19 (76%) had a viral load below 50 copies/mL. One child was perinatally HIV-infected. Three women were exposed to efavirenz throughout the first 6 weeks of pregnancy. EFV was well tolerated and among the 25 infants no congenital anomalies or newborn complications were reported.
Changes in efavirenz pharmacokinetics during pregnancy compared to postpartum are not sufficiently large enough to warrant a dose adjustment during pregnancy.
efavirenz; pregnancy; pharmacokinetics; HIV; prevention of mother-to-child transmission of HIV
Improved antiretroviral therapies are needed for the treatment of HIV infected infants due to rapid disease progression and drug resistance from perinatal exposure to antiretrovirals. We examined longitudinal pharmacokinetic (PK) data from a clinical trial of lopinavir/ritonavir in HIV-infected infants initiating therapy less than 6 months of age. A population PK analysis was performed using NONMEM to characterize changes in lopinavir (LP V) PK relating to maturational changes in infants, and to assess dosing requirements in this population. We also investigated the relationship between LPV PK and viral dynamic response. Age and ritonavir concentrations were the only significant covariates found. Population PK of LPV was characterized by high apparent clearance in young infants which decreased with age. Although younger infants had lower LPV concentrations, viral dynamics did not correlate with initial LPV exposure. Monte Carlo simulations demonstrated that WHO weight band-based dosing recommendations predicted therapeutic LPV concentrations and provided comparable drug exposure levels comparable to those resulting from US Food and Drug Administration (FDA)-suggested dosing regimens.
population pharmacokinetics; HIV; WHO; AIDS; antiretroviral
Lopinavir/ritonavir (Kaletra®) is first line therapy for pediatric HIV infection. In clinical practice, Kaletra® tablets are occasionally crushed for pediatric administration. This study compared lopinavir/ritonavir exposure between whole and crushed tablets in HIV-infected children.
This was a randomized, open-label, cross-over study of pediatric patients taking lopinavir/ritonavir as part of their antiretroviral regimen. Each subject had two separate (within 30 days) steady-state 12-hour pharmacokinetic (PK) studies with crushed and whole 200/50 mg lopinavir/ritonavir tablets.
PK blood samples were drawn at 0 (pre-dose), 1, 2, 4, 6, 8, and 12 hours post-dose. Lopinavir and ritonavir plasma concentrations measured by high performance liquid chromatography were used to calculate non-compartmental area under the concentration versus time curve (AUC) and clearance (CL/F). Wilcoxon signed-rank tests compared PK values between crushed and whole tablets.
Twelve children, median age of 13 years (10–16 years), took 550/138 mg/m2/day lopinavir/ritonavir divided every 12 hours. The median lopinavir AUC following crushed and whole tablets were 92 mg*hr/L and 144 mg*hr/L, respectively, with an AUC ratio of 0.55 (p=0.003). Median ritonavir AUC of crushed and whole tablets were 7 mg*hr/L and 13.3 mg*hr/L, respectively, with an AUC ratio of 0.53 (p=0.006).
Administration of crushed 200/50 mg lopinavir/ritonavir tablets to children significantly reduced lopinavir and ritonavir exposure with a decrease in AUC by 45% and 47%, respectively. The administration of crushed tablets would require higher doses and therapeutic drug monitoring to ensure adequate lopinavir exposure in patients requiring this practice. The use of crushed lopinavir/ritonavir tablets should be avoided, if possible.
lopinavir; ritonavir; pharmacokinetics; pediatrics
Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events.
Premature and term infants <91 days of age hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20–30 mg/kg of body weight every 8–12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM®.
Two hundred infants were enrolled and received study drug. One hundred eighty-eight infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23–40) weeks and 21 (1–92) days, respectively. In the final PK model, meropenem clearance (CL) was strongly associated with serum creatinine (SCR) and postmenstrual age (PMA) (CL [L/h/kg] = 0.12*[(0.5/SCR)**0.27]*[(PMA/32.7)**1.46]). Meropenem concentrations remained >4 μg/mL for 50% of the dose interval and >2 μg/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5–148).
Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.
enterocolitis; necrotizing; infant; premature; cerebrospinal fluid
Antiretrovirals that reach higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV in CSF and possibly better neurocognitive performance. The objective of this study was to determine whether amprenavir (APV) concentrations in CSF are in the therapeutic range. Individuals were selected based on the use of regimens that included fosamprenavir (FPV), a prodrug of APV, and the availability of stored CSF and matched plasma. Total APV was measured in 119 matched CSF-plasma pairs from 75 subjects by high-performance liquid chromatography (HPLC) (plasma) or liquid chromatography tandem mass spectrometry (LC/MS/MS) (CSF). Concentrations were compared to the 50% inhibitory concentration (IC50) for wild-type HIV (5.6 ng/ml). Subjects were predominantly middle-aged (median 44 years) white (57%) men (78%) with AIDS (77%). APV was detected in all but 4 CSF specimens, with a median concentration of 24.8 ng/ml (interquartile range [IQR], 16.2 to 44.0). The median CSF-to-plasma ratio was 0.012 (IQR, 0.008 to 0.018). CSF concentrations correlated with plasma concentrations (rho = 0.61; P < 0.0001) and with postdose sampling interval (rho = −0.29; P = 0.0019). APV concentrations in CSF exceeded the median IC50 for wild-type HIV in more than 97% of CSF specimens with detectable APV by a median of 4.4-fold (IQR, 2.9 to 7.9). We conclude that administration of fosamprenavir should contribute to control of HIV replication in the central nervous system (CNS) as a component of effective antiretroviral regimens.
Until approximately 15 years ago, sponsors rarely included children in the development of therapeutics. US and European legislation has resulted in an increase in the number of pediatric trials and specific label changes and dosing recommendations, although infants remain an understudied group. The lack of clinical trials in children is partly due to specific challenges in conducting trials in this patient population. Therapeutics in special populations, including premature infants, obese children and children receiving extracorporeal life support, are even less studied. National research networks in Europe and the USA are beginning to address some of the gaps in pediatric therapeutics using novel clinical trial designs. Recent innovations in pediatric clinical trial design, including sparse and scavenged sampling, population pharmacokinetic analyses and ‘opportunistic’ studies, have addressed some of the historical challenges associated with clinical trials in children.
clinical trial simulation; opportunistic study; pediatrics; pharmacodynamics; pharmacokinetics; pharmacometrics; therapeutics
Alternatives to the available stavudine-containing paediatric fixed-dose combination (FDC) tablets are rapidly needed due to concerns regarding the cumulative toxicity of long-term stavudine exposure. We report the bioavailability and short-term safety of a novel paediatric FDC tablet of zidovudine (ZDV)/lamivudine (3TC)/nevirapine (NVP; 30/15/28 mg) in HIV-infected children.
In this Phase I/II open-label pharmacokinetic study, 42 children weighing 6–30 kg treated with NVP-based HAART for ≥4 weeks were randomized to receive the FDC tablets (GPO-VIR Z30) or the liquid formulations. Dosing was weight-based. Intensive 12-h blood sampling was performed after 2 weeks; subjects then crossed-over to the alternate formulation at equal doses and sampling repeated 2 weeks later. Pharmacokinetic parameters were determined by non-compartmental analysis. Buccal-swab samples were collected for cytochrome P450 (CYP)2B6 polymorphism analysis.
With the FDC tablet, the geometric mean (90% CI) area under the curve (AUC) for ZDV, 3TC and NVP was 1.58 (1.49–1.68), 7.78 (7.38–8.19) and 68.88 (62.13–76.36) μg•h/ml, respectively. Rules for NVP therapeutic inadequacy were defined a priori, and despite lower NVP exposure with the tablet (P<0.001), the levels remained therapeutically adequate. ZDV AUC was similar between formulations. 3TC exposure was significantly higher with the tablet but comparable to historical data in adults and children taking branded tablets. While receiving the tablet, NVP AUC in children with CYP2B 516 GG (45%), GT (45%) and TT (10%) genotypes were 67.0, 74.5 and 106.4 μg•h/ml, respectively (P=0.04).
Disparities in drug exposure between formulations were observed; however, the FDC tablet delivered therapeutically adequate exposures of each drug and could well play an important role in simplifying antiretroviral treatment for children.
Plasma concentrations of several protease inhibitors are decreased during pregnancy. Few data are available describing atazanavir exposure during pregnancy, especially when used in combination with tenofovir, whose coadministration with atazanavir results in decreased atazanavir exposure.
IMPAACT 1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included two cohorts receiving atazanavir/ritonavir 300mg/100mg once daily during the third trimester through 6-12 weeks postpartum either with or without tenofovir.
Intensive steady-state 24-hour pharmacokinetic profiles were performed during the third trimester and at 6-12 weeks postpartum. Atazanavir was measured by reverse-phase HPLC with a detection limit of 0.13 mcg/mL. Pharmacokinetic targets were the estimated 10th percentile atazanavir AUC (29.4 mcg*hr/mL) in non-pregnant historical controls taking the standard dose (mean AUC=57 mcg*hr/mL) and a trough concentration of 0.15 mcg/mL, the concentration target used in therapeutic drug monitoring programs. Infant bilirubin concentrations were measured at 24-48 hours and 4-6 days after birth.
Atazanavir pharmacokinetic data were available for 38 women (18 without tenofovir, 20 with tenofovir. Median atazanavir AUC was reduced during the third trimester compared to postpartum for subjects not receiving tenofovir (41.9 vs 57.9 mcg*hr/mL, p=.02) and for subjects receiving tenofovir (28.8 vs. 39.6 mcg*hr/mL, p=.04). During the third trimester, AUC was below the target in 33% (6/18) of women not receiving tenofovir and 55% (11/20) of women receiving tenofovir. Trough concentration was below the target in 6% (1/18) of women not receiving tenofovir and 15% (3/20) of women receiving tenofovir. The median (range) ratio of cord blood/maternal atazanavir concentration in 29 paired samples was 0.18 (0 - 0.45). No excessive infant bilirubin concentrations were observed.
Atazanavir exposure is reduced by pregnancy and by concomitant tenofovir use. A dose increase of atazanavir/ritonavir to 400mg/100mg may be necessary in pregnant women to ensure atazanavir exposure equivalent to that seen in nonpregnant adults, especially for pregnant women who are antiretroviral-experienced and/or who are also receiving tenofovir.
atazanavir; tenofovir; pharmacokinetics; pregnancy; HIV; mother to child transmission
Purpose of review
Systemic infections in premature and term infants cause significant morbidity and mortality in spite of appropriate antimicrobial therapy. Consequently, immunotherapy has emerged as a potential adjuvant therapeutic modality to reduce the incidence and mortality associated with neonatal sepsis.
The most recent findings during the review period include systematic reviews of previously published trials evaluating the use of intravenous immunoglobulin and colony stimulating factors in neonatal sepsis. In addition, the most recent trials describing the use of anti-staphylococcal antibodies, probiotics, glutamine supplementation, recombinant human protein C, and lactoferrin in the prevention and treatment of neonatal sepsis have been reviewed.
Immunotherapy used as an adjuvant for the prevention and treatment of neonatal sepsis holds promise. Clinical trials specifically designed towards the neonatal population and appropriately powered to detect treatment differences are necessary prior to universal recommendation of these therapies in the nursery.
newborn; prematurity; systemic infection; immune system
According to the multi-process theory of prospective memory (ProM), time-based tasks rely more heavily on strategic processes dependent on prefrontal systems than do event-based tasks. Given the prominent frontostriatal pathophysiology of HIV infection, one would expect HIV-infected individuals to demonstrate greater deficits in time-based versus event-based ProM. However, the two prior studies examining this question have produced variable results. We evaluated this hypothesis in 143 individuals with HIV infection and 43 demographically similar seronegative adults (HIV−) who completed the research version of the Memory for Intentions Screening Test, which yields parallel subscales of time- and event-based ProM. Results showed main effects of HIV serostatus and cue type, but no interaction between serostatus and cue. Planned pair-wise comparisons showed a significant effect of HIV on time-based ProM and a trend-level effect on event-based ProM that was driven primarily by the subset of participants with HIV-associated neurocognitive disorders. Nevertheless, time-based ProM was more strongly correlated with measures of executive functions, attention/working memory, and verbal fluency in HIV-infected persons. Although HIV-associated deficits in time- and event-based ProM appear to be of comparable severity, the cognitive architecture of time-based ProM may be more strongly influenced by strategic monitoring and retrieval processes.
AIDS dementia complex; Episodic memory; Executive functions; Neuropsychological assessment
To evaluate UDP-glucuronyltransferase (UGT) activity and the pharmacokinetics of a single oral dose of acetaminophen (APAP) in children with non-alcoholic fatty liver disease (NAFLD).
Twelve boys 10–17 years old with biopsy-proven NAFLD and 12 age and gender-matched controls without NAFLD were recruited. Following administration of a single oral dose of APAP (5mg/kg, maximum 325mg), APAP and its glucuronide metabolite (APAP-G) were measured in plasma, urine, and sputum at various intervals up to 24 hours. The activity of UGT was estimated by the plasma ratio of APAP-G to APAP at 4 hours.
Following administration of APAP, children with NAFLD had significantly higher concentrations of APAP-G in serum (p=.0071) and urine (p=.0210) compared to controls. No significant differences in APAP pharmacokinetics parameters were observed between the two groups.
APAP glucuronidation is altered in children with fatty liver disease. Despite the altered disposition of this metabolite, the pharmacokinetics of a single 5 mg/kg dose of APAP is the same in children with NAFLD as in children with normal liver function.
nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; acetaminophen; UDP-glucuronyltransferase; pharmacokinetics; pediatrics
Reduced lopinavir concentrations have been demonstrated with use of the capsule formulation during the third trimester of pregnancy. This study determined lopinavir exposure with an increased dose of the new tablet formulation during the third trimester.
International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is a prospective nonblinded pharmacokinetic study in HIV-infected pregnant women, including a cohort receiving 2 lopinavir/ritonavir tablets (400 mg/100 mg) twice daily during the second trimester, 3 tablets (600 mg/150 mg) twice daily during the third trimester, and 2 tablets (400 mg/100 mg) twice daily postdelivery through 2 weeks postpartum.
Steady-state 12-hour pharmacokinetic profiles were performed during pregnancy and at 2 weeks postpartum. Lopinavir and ritonavir were measured by reverse-phase high-performance liquid chromatography (detection limit, 0.09 mcg/mL).
Thirty-three women were studied. Median lopinavir AUC for the second trimester (n = 11), third trimester (n = 33), and postpartum (n = 27) were 72, 96, and 133 mcg·hr/mL, respectively. Median minimum lopinavir concentrations were 3.4, 4.9, and 6.9 mcg/mL.
The higher lopinavir/ritonavir tablet dose (600 mg/150 mg) provided exposure during the third trimester similar to the average AUC (98 mcg·hr·mL−1) in nonpregnant adults taking 400 mg/100 mg twice daily. The higher dose should be used during the second and third trimesters of pregnancy. Postpartum dosing can be reduced to standard dosing before 2 weeks postpartum.
HIV; lopinavir; mother-to-child transmission; pharmacokinetics; pregnancy
Lopinavir/ritonavir; pharmacokinetics; infants; HIV-1
The objective of this research was to identify the impact of genetic variants of P-glycoprotein (ABCB1) and cytochrome P450 (CYP) on nelfinavir pharmacokinetics and response to highly active antiretroviral therapy (HAART) in HIV-1–infected children.
HIV-1–infected children (n = 152) from Pediatric AIDS Clinical Trial Group 366 or 377 receiving nelfinavir as a component of HAART were evaluated. Genomic DNA was assayed for ABCB1 and CYP genetic variants using real-time polymerase chain reaction Nelfinavir oral clearance (CL/F), M8 to nelfinavir ratios, CD4+ T cells, and HIV-1-RNA were measured during HAART.
Nelfinavir CL/F and M8 to nelfinavir ratios were significantly associated with the CYP2C19-G681A genotypes (P < 0.001). Furthermore, the CYP2C19-G681A genotype was related to virologic responses at week 24 (P = 0.01). A multivariate analysis demonstrated that age (P = 0.03), concomitant protease inhibitor use (P < 0.001), and the CYP2C19-G681A genotype (P < 0.001) remained significant covariates associated with nelfinavir CL/F.
CYP2C19 genotypes altered nelfinavir pharmacokinetics and the virologic response to HAART in HIV-1–infected children. These findings suggest that CYP2C19 genotypes are important determinants of nelfinavir pharmacokinetics and virologic response in HIV-1-infected children.
ABCB1; CYP2C19; children; nelfinavir; virologic response
Candida infections are common and often fatal in infants and neonates. Anidulafungin has excellent activity against Candida sp, but unknown pharmacokinetics and safety in infants and neonates.
Determine the pharmacokinetics and safety of anidulafungin in infants and neonates at risk for invasive candidiasis.
Intravenous anidulafungin (1.5 mg/kg/day maintenance dose) was administered to 15 infants and neonates over 3 to 5 days. Plasma samples were obtained following the first and third to fifth dosesPharmacokinetic parameters were determined by non-compartmental analysis. Safety was assessed using National Cancer Institute common toxicity criteria.
Drug exposure was similar between neonates and infants: median area under the curve (range) was 75 (30–109) μg*h/mL and 98 (55–278) μg*h/mL (P=0.12), respectively. No drug-related serious adverse events were observed.
Neonates and infants receiving 1.5 mg/kg/day have similar anidulafungin exposures compared to children receiving similar weight-based dosing and adult patients receiving 100 mg/day.
antifungal agents; prematurity; infection; candidiasis; echinocandins
HIV-associated neurocognitive disorders continue to be common. Antiretrovirals that achieve higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV and improved cognition. The objective of this study was to measure total raltegravir (RAL) concentrations in CSF and to compare them with matched concentrations in plasma and in vitro inhibitory concentrations. Eighteen subjects with HIV-1 infection were enrolled based on the use of RAL-containing regimens and the availability of CSF and matched plasma samples. RAL was measured in 21 CSF and plasma pairs by liquid chromatography-tandem mass spectrometry, and HIV RNA was detected by reverse transcription-PCR (RT-PCR). RAL concentrations were compared to the 50% inhibitory concentration (IC50) for wild-type HIV-1 (3.2 ng/ml). Volunteers were predominantly middle-aged white men with AIDS and without hepatitis C virus (HCV) coinfection. The median concurrent CD4+ cell count was 276/μl, and 28% of CD4+ cell counts were below 200/μl. HIV RNA was detectable in 38% of plasma specimens and 4% of CSF specimens. RAL was present in all CSF specimens, with a median total concentration of 14.5 ng/ml. The median concentration in plasma was 260.9 ng/ml, with a median CSF-to-plasma ratio of 0.058. Concentrations in CSF correlated with those in with plasma (r2, 0.24; P, 0.02) but not with the postdose sampling time (P, >0.50). RAL concentrations in CSF exceeded the IC50 for wild-type HIV in all specimens by a median of 4.5-fold. RAL is present in CSF and reaches sufficiently high concentrations to inhibit wild-type HIV in all individuals. As a component of effective antiretroviral regimens or as the main antiretroviral, RAL likely contributes to the control of HIV replication in the nervous system.
The World Health Organization endorses the use of artemisinin-based combination therapy for treatment of acute uncomplicated falciparum malaria in the second and third trimesters of pregnancy. However, the effects of pregnancy on the pharmacokinetics of artemisinin derivatives, such as artesunate (AS), are poorly understood. In this analysis, the population pharmacokinetics of oral AS, and its active metabolite dihydroartemisinin (DHA), were studied in pregnant and non-pregnant women at the Kingasani Maternity Clinic in the DRC.
Data were obtained from 26 pregnant women in the second (22 - 26 weeks) or the third (32 - 36 weeks) trimester of pregnancy and from 25 non-pregnant female controls. All subjects received 200 mg AS. Plasma AS and DHA were measured using a validated LC-MS method. Estimates for pharmacokinetic and variability parameters were obtained through nonlinear mixed effects modelling.
A simultaneous parent-metabolite model was developed consisting of mixed zero-order, lagged first-order absorption of AS, a one-compartment model for AS, and a one-compartment model for DHA. Complete conversion of AS to DHA was assumed. The model displayed satisfactory goodness-of-fit, stability, and predictive ability. Apparent clearance (CL/F) and volume of distribution (V/F) estimates, with 95% bootstrap confidence intervals, were as follows: 195 L (139-285 L) for AS V/F, 895 L/h (788-1045 L/h) for AS CL/F, 91.4 L (78.5-109 L) for DHA V/F, and 64.0 L/h (55.1-75.2 L/h) for DHA CL/F. The effect of pregnancy on DHA CL/F was determined to be significant, with a pregnancy-associated increase in DHA CL/F of 42.3% (19.7 - 72.3%).
In this analysis, pharmacokinetic modelling suggests that pregnant women have accelerated DHA clearance compared to non-pregnant women receiving orally administered AS. These findings, in conjunction with a previous non-compartmental analysis of the modelled data, provide further evidence that higher AS doses would be required to maintain similar DHA levels in pregnant women as achieved in non-pregnant controls.
To investigate the longitudinal pharmacokinetics, safety and efficacy of lopinavir/ritonavir (LPV/r) in HIV-infected infants initiating combination antiretroviral therapy (cART) between 2 weeks and 6 months of age.
A prospective, open-label, multicenter Phase I/II study of LPV/r-based cART at a dose of 300/75 mg/m2/dose LPV/r twice daily. Intensive pharmacokinetic sampling at 12 months of age and quarterly predose LPV concentrations were collected and safety, virologic and immunologic responses were monitored every 4–12 weeks up to 252 weeks.
Thirty-one HIV-infected infants enrolled into two age cohorts, 14 days to <6 weeks and 6 weeks to <6 months; 29 completed ≥48 weeks of follow-up (median=123 weeks, range 4–252). At 12 months of age, median LPV area under the curve was comparable for both age cohorts and similar to older children and adults. At week 48, 22 of 31 patients (71%) had HIV-1 RNA <400 copies/ml and 11 of 15 (73%) had <50 copies/ml; 29 of 31 achieved HIV-1 RNA <400 copies/ml on study treatment and 19 (66%) remained durably suppressed until the end of study; viral suppression correlated with a higher percentage of predose time points exceeding the LPV target of 1 μg/ml (92 vs. 71%, P=0.002).
LPV/r at 300/75 mg/m2/dose as part of a cART regimen resulted in viral suppression through 96 weeks of treatment in >65% of young infants. Due to initially low LPV exposure in infants <6 weeks of age, frequent dose adjustment for weight gain is advisable and consideration should be given to studying a higher dose for very young infants.
AIDS; HIV-1; initiation of antiretroviral therapy in young infants; lopinavir/ritonavir; pharmacokinetics of antiretrovirals