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Antimicrob Agents Chemother. 1999 March; 43(3): 603–608.
PMCID: PMC89167

Safety and Pharmacokinetics of Abacavir (1592U89) following Oral Administration of Escalating Single Doses in Human Immunodeficiency Virus Type 1-Infected Adults

Abstract

Abacavir (1592U89) is a nucleoside analog reverse transcriptase inhibitor that has been demonstrated to have selective activity against human immunodeficiency virus (HIV) in vitro and favorable safety profiles in mice and monkeys. A phase I study was conducted to evaluate the safety and pharmacokinetics of abacavir following oral administration of single escalating doses (100, 300, 600, 900, and 1,200 mg) to HIV-infected adults. In this double-blind, placebo-controlled study, subjects with baseline CD4+ cell counts ranging from <50 to 713 cells per mm3 (median, 315 cells per mm3) were randomly assigned to receive abacavir (n = 12) or placebo (n = 6). The bioavailability of the caplet formulation relative to that of the oral solution was also assessed with the 300-mg dose. Abacavir was well tolerated by all subjects; mild to moderate asthenia, abdominal pain, headache, diarrhea, and dyspepsia were the most frequently reported adverse events, and these were not dose related. No significant clinical or laboratory abnormalities were observed throughout the study. All doses resulted in mean abacavir concentrations in plasma that exceeded the mean 50% inhibitory concentration (IC50) for clinical HIV isolates in vitro (0.07 μg/ml) for almost 3 h. Abacavir was rapidly absorbed following oral administration, with the time to the peak concentration in plasma occurring at 1.0 to 1.7 h postdosing. Mean maximum concentrations in plasma (Cmax) and the area under the plasma concentration-time curve from time zero to infinity (AUC0–∞) increased slightly more than proportionally from 100 to 600 mg (from 0.6 to 4.7 μg/ml for Cmax; from 1.0 to 15.7 μg · h/ml for AUC0–∞) but increased proportionally from 600 to 1,200 mg (from 4.7 to 9.6 μg/ml for Cmax; from 15.7 to 32.8 μg · h/ml for AUC0–∞). The elimination of abacavir from plasma was rapid, with an apparent elimination half-life of 0.9 to 1.7 h. Abacavir was well absorbed, with a relative bioavailability of the caplet formulation of 96% versus that of an oral solution (drug substance in water). In conclusion, this study showed that abacavir is safe and is well tolerated by HIV-infected subjects and demonstrated predictable pharmacokinetic characteristics when it was administered as single oral doses ranging from 100 to 1,200 mg.

Abacavir (formerly 1592U89), (−)-(1S,4R)-4-[2-amino-6-(cy-clopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, is a synthetic carbocyclic nucleoside analog that inhibits human immunodeficiency virus type 1 (HIV-1) replication with low levels of cytotoxicity to MT4 cells (a transformed human leukemic cell line), peripheral blood lymphocytes, and macrophages (3). Abacavir is phosphorylated in a unique stepwise manner to produce the active moiety, carbocyclic guanosine triphosphate (3, 5). The mechanism of anti-HIV activity for abacavir has been shown to be substrate inhibition of HIV reverse transcriptase (RT) by carbocyclic guanosine triphosphate, resulting in chain termination and interruption of the viral replication cycle. When tested with normal human peripheral blood lymphocytes against fresh clinical isolates of HIV-1 obtained from antiretroviral drug-naive patients, the mean 50% inhibitory concentration (IC50) was 0.26 μM (0.07 μg/ml); the corresponding IC50s of zidovudine (ZDV), didanosine (ddI), and zalcitabine (ddC) were 0.23, 0.49, and 0.03 μM, respectively (3). Abacavir has been shown to have similar activities against HIV strains that were resistant to ZDV, lamivudine (3TC), ddI, ddC, and a number of nonnucleoside RT inhibitors. Studies have shown that abacavir synergistically inhibits HIV-1 IIIB in MT4 cells when it is combined with ZDV, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor amprenavir (141W94) (3, 11). Combinations of abacavir with 3TC, ddI, ddC, or stavudine were additive to synergistic (3).

Abacavir is a low-molecular-weight compound (molecular weight, 281.4) that is lipophilic (the 1-octanol-0.1 M sodium phosphate [pH 7.4] partition coefficient [log P] is 1.22) and that is a weak base (pKa = 5.01). It has good solubility in water (>80 mM at 25°C) and is not protonated at a neutral pH. Abacavir is significantly more lipophilic than ZDV (log P, 0.09), the most lipophilic of the currently approved nucleoside RT inhibitors. Studies have shown that abacavir, administered as the succinate salt, has high oral bioavailability (>76%) in mice and monkeys and can penetrate the blood-brain barrier as well as ZDV can (6). Abacavir is primarily eliminated by metabolism, with only approximately 11 to 13% of the dose being recovered as unchanged drug in the urine of mice and monkeys (7). The two principal metabolites of abacavir identified in monkey urine were 5′-carboxylate (20% of the dose administered) and 5′-glucuronide (32% of the dose administered).

In preclinical studies, abacavir has been shown to have minimal toxicity in in vitro cytotoxic, cytogenetic, and mutagenic assays and in animals (2, 6). In monkeys dosed orally with abacavir (50, 140, and 420 mg/kg of body weight/day) for 30 and 90 days, reversible increases in serum triglyceride levels were noted at the intermediate and highest doses. In addition, the toxicities observed with other nucleoside RT inhibitors—neurophysiological deterioration and renal, cardiac, and hematopoietic toxicities—were not observed with the highest dose tested.

The first phase I study (Glaxo Wellcome protocol 131-001), described in this report, was conducted to determine the safety and pharmacokinetics of single escalating oral doses of abacavir in HIV-infected subjects.

(This work was presented in part at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., 17 to 20 September 1995 [10].)

MATERIALS AND METHODS

Study population.

Eligible subjects included HIV-positive, asymptomatic male and female subjects of any race between 13 and 55 years of age. Written informed consent was obtained from all participants, and the study was approved by the institutional review boards of the Georgetown University Medical Center and the University of Kansas. Each center enrolled nine subjects. The subjects had tested positive for antibody to HIV-1 or had clinical evidence of HIV infection as defined by the Centers for Disease Control and Prevention (CDC) HIV classification guidelines. Subjects were excluded from enrollment if they had a history of pancreatitis or hepatitis within the last 5 years, an absolute neutrophil count of <1,500 cells/mm3, a hemoglobin level of <10 g/dl (for women) or <11 g/dl (for men), a platelet count of <100,000 cells/mm3, serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels more than three times the upper limit of normal, and an estimated creatinine clearance of <50 ml/min. Subjects were also excluded from the study if they had debilitating HIV infection or a malabsorption disorder, were active substance or alcohol abusers, or were pregnant or nursing. All prescription and over-the-counter medications were withheld for 48 h (or 24 h for antiretroviral agents) prior to dosing and during the day of abacavir dosing.

Study design.

This was a double-blind, placebo-controlled, parallel, rising-dose study. The subjects were randomly assigned 2:1 to receive abacavir or matching placebo for all caplet doses. Each subject received five single escalating oral doses of abacavir separated by at least a 6-day washout period and were given the option to receive a sixth dose. The abacavir doses administered sequentially were 100, 300, 600, 900, and 1,200 mg as caplets and 300 mg as a solution. Abacavir was supplied as 100-mg white, biconvex caplets or as a 50-ml solution by Glaxo Wellcome Inc., Research Triangle Park, N.C. Abacavir placebo was supplied as matching caplets, but no placebo solution was supplied. Each caplet contained 100 mg of abacavir (free base) as the succinate salt, and the oral solution was prepared as abacavir succinate dissolved in water to a concentration of 6 mg/ml (as the free base content). Each subject took the abacavir doses (1 to 12 caplets) with 200 ml of water and fasted for another 3 h postdosing.

Within 14 days of administration of the first dose, the subjects underwent a screening evaluation, including a medical history, physical examination, and measurement of clinical laboratory parameters. The subjects were admitted to the clinical research unit in the morning after an overnight fast (at least 8 h) and remained at the site until 24 h postdosing. The subjects were instructed to return to the study site at least 6 days later to begin the next dosing period. At 7 to 10 days after the completion of the last dosing period, subjects returned for a follow-up examination that was similar to that used for the screening evaluation.

Blood samples.

Blood samples (5 ml each) were collected by venipuncture and placed into heparin-containing Vacutainer tubes immediately prior to dosing and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, and 24.0 h after the administration of each dose. Blood samples were kept at 4°C upon collection and were centrifuged within 1 h of collection to separate the plasma, which was stored at −40°C until it was analyzed. The stability of abacavir in plasma samples has been validated at −40°C for 11 months, which covered the period from the time of sample collection to the time of assay.

Assay for plasma samples.

Plasma abacavir concentrations were determined by a validated reversed-phase high-performance liquid chromatography (HPLC) assay with UV detection. Briefly, analytical stock standard and control solutions were prepared separately in HPLC-grade water. The appropriate volumes of the stock solutions were spiked into normal, blank, pooled human plasma to provide working standards or controls. The quantifiable range was 25 to 5,000 ng/ml, and the control concentrations were 40, 250, and 2,500 ng/ml. To 0.2 ml of standard, control, or unknown samples, 0.1 ml of 10% trichloroacetic acid was added, and the components were mixed by vortexing and were centrifuged at 8,800 × g for 10 min. The supernatants were transferred into injection vials (containing limited-volume inserts) and were placed in an autosampler. The supernatants (0.1 ml) were injected at 15-min intervals, and the chromatographic separation was achieved on a Rainin C18 Microsorb MV column. The mobile phase consisted of 40% methanol and 0.3% (vol/vol) triethylamine (TEA) at a constant flow rate of 1.0 ml/min. Abacavir was detected by measuring the UV absorbance at 284 nm. The approximate retention time for abacavir was 9 min under these conditions. The interday precisions (percent coefficients of variation) calculated from the quality control samples were 7.7% at 0.04 μg/ml, 3.6% at 0.25 μg/ml, and 3.0% at 2.50 μg/ml; and the interday variabilities (biases) were −2.0, −2.4, and −5.8%, respectively.

Safety evaluation.

The safety and tolerability of single escalating doses of abacavir were evaluated on the basis of adverse experience reports, measurements of vital signs and clinical laboratory test values and the results of physical examinations and electrocardiograms. In each dosing period, the severity (mild, moderate, or severe), duration, and potential relationship to the study drug (unrelated or possibly, probably, or almost certainly related, according to the investigator) of any adverse events were recorded. Vital sign determinations (sitting blood pressure and sitting pulse), routine hematologic studies (complete blood count with differential, mean corpuscular volume, and platelet count), serum chemistry studies (electrolyte, AST, ALT, total bilirubin, creatinine, albumin, glucose, alkaline phosphatase, and serum amylase levels), and urinalysis (dipstick for protein and blood) were performed at screening, prior to the administration of study drug in each dosing period, and at a follow-up visit.

Pharmacokinetic analysis.

The plasma concentration-time data for abacavir were analyzed by standard noncompartmental pharmacokinetic methods. The peak concentration in plasma (Cmax) and the time to Cmax (Tmax) were obtained from direct inspection of the plasma concentration-time profile. Estimates of the apparent terminal elimination half-life (t1/2β) were calculated as ln(2)/λz, where λz is the terminal elimination rate constant and is a first-order rate constant determined from the negative of the slope of the linear regression line of the apparent terminal linear portion of the log concentration-versus-time curve. The data points for inclusion in the linear regression line were selected by starting with the last three measurable concentrations, and points were added on the basis of changes in the regression slope, regression R2, negative regression residual, and Cmax. These points were visually inspected, with no changes made to the selected points. The area under the plasma concentration-time curve from time zero to time t (AUC0–t), where t is the last time point with a measurable concentration of the compound of interest, was calculated by using the linear trapezoidal method. The AUC from time zero to infinity (AUC0–∞) was then determined as AUC0–t + Clastz, where Clast is the last measurable concentration of the compound of interest. The apparent clearance from plasma (CL/F) was calculated as the dose divided by AUC0–∞ and was then normalized to body weight.

Statistical analysis.

Cmax and AUC0–∞ values were dose normalized to 100 mg, and all pharmacokinetic parameters (except Tmax) were log transformed (base e) prior to analysis. A power model was used to assess the extent of dose proportionality for Cmax and AUC0–∞ across treatments, as follows: Yij = αi (Dj)βi. The log-transformed model is log (Yij) = log (αi) + βilog (Dj) + eij, where Dj is dose level j and Yij is the value of the pharmacokinetic parameter for subject i at dose level j; αi and βi are the intercept and slope for subject i, respectively; and eij is the residual error. The power model was fitted by restricted maximum likelihood methods with unrestricted variance structure by using SAS PROC MIXED (version 6.09; SAS Institute, Inc., Cary, N.C.). A population average estimate of β and its 90% confidence interval (CI) were calculated from the individual β values of both parameters for all doses and for doses from 600 to 1,200 mg. The degree of departure of the slope β from unity was the primary assessment of nonproportionality. Parameters were considered dose proportional if the resultant 90% CI of the population average estimate of β included 1.0.

Differences between treatments with respect to AUC0–∞, Cmax, t1/2β, and CL/F values were also assessed by analysis of variance by using PROC MIXED (or mixed effects linear models) from SAS. The model included the treatments as fixed effects and subjects as the random effect. Descriptive statistics, including geometric least square means (LSMs) and their 95% CIs, were calculated for each treatment. To determine dose proportionality with respect to the 300-mg dose used in subsequent clinical trials, each dose was compared with the 300-mg dose on a pairwise basis by calculating the ratio of the test dose LSM to the reference dose LSM and the resultant 90% CI for each parameter of interest (except Tmax). For dose-normalized AUC0–∞ and Cmax estimates, the degree of departure from dose proportionality for each comparison was determined by the deviation of the LSM ratio from 1. Nonparametric methods were used to compute the 95% CI for the untransformed median Tmax values of each treatment. A 90% CI for the median difference in Tmax between treatments was calculated by using the Wilcoxon signed rank test. To assess the bioavailability of the caplet formulation relative to that of the oral solution, the statistical procedures were repeated by using a model that was restricted to these 300-mg treatments.

RESULTS

Subject demographics and characteristics.

Eighteen subjects (15 men and 3 women) were enrolled in this study. Four subjects in the abacavir-treated group were prematurely discontinued from the study for reasons unrelated to treatment with the study drug. The reasons for premature discontinuation included loss of intravenous access (one subject after the first dose), withdrawal of consent (two subjects after the second dose), and failure to return for treatment after a brief hiatus to recover from giardiasis (one subject after the fourth dose). Two subjects elected not to receive the 300-mg dose of abacavir in solution. All subjects in the placebo group completed the study. The treatment groups were comparable at the baseline with respect to demographic variables, HIV risk factors, and CDC classification (Table (Table1).1).

TABLE 1
Demographics and characteristics of the subjects

Safety evaluation.

Abacavir was well tolerated at single oral doses of up to 1,200 mg. There were no significant differences between groups in the type or frequency of adverse events. Ten of 12 subjects in the abacavir group and 4 of 6 subjects in the placebo group reported at least one adverse event during the study. None were serious, and there were no withdrawals due to adverse events. Most were mild to moderate in intensity, and those assessed as possibly related to abacavir included asthenia (33%), abdominal pain (33%), headache (25%), diarrhea (17%), and dyspepsia (17%). Three subjects each reported one adverse event that was classified as severe in intensity: headache (possibly related to abacavir), diarrhea (unrelated to abacavir), and diarrhea (possibly related to placebo).

There were no significant differences between groups with regard to hematologic findings, clinical chemistry findings, vital signs, physical examination findings, or urine dipstick results. Four subjects receiving abacavir had abnormal clinical laboratory results. Two subjects had mild elevations in AST and ALT levels (grade 1) at the baseline and throughout the study, and these did not change substantially following treatment; one of these subjects was also a diabetic who was not compliant with his diet during the study and who had progressively elevated glucose values (grade 3). Hemolyzed blood samples from two subjects severely altered laboratory tests and resulted in numerous abnormal test results; one of these subjects also had mild elevations in amylase levels (grade 1) at the baseline and throughout the study, and these did not change substantially following treatment. One subject receiving placebo had progressively increasing AST and ALT levels (grades 1 to 4) during the study.

Pharmacokinetic evaluation.

Mean plasma abacavir concentration-versus-time profiles for the 100- to 1,200-mg doses are depicted in Fig. Fig.1.1. Following oral administration, abacavir was rapidly absorbed, achieving measurable concentrations in plasma by the first sampling time (15 min). In general, plasma abacavir concentrations fell below detectable concentrations (0.025 μg/ml) at or after 12 h postdosing. In addition, all abacavir doses resulted in mean concentrations in plasma that exceeded the mean IC50 for clinical HIV isolates in vitro (0.07 μg/ml) (Fig. (Fig.1).1).

FIG. 1
(A) Mean ± standard deviation plasma abacavir concentration-versus-time curves following oral administration of single escalating doses under fasting conditions. (B) Logarithmic plot of mean plasma abacavir concentration-time profiles for each ...

Mean pharmacokinetic parameter estimates for all doses are presented in Table Table2.2. Intersubject variability was large for most pharmacokinetic parameters, with the largest variability noted for the lowest dose (100 mg).

TABLE 2
Mean pharmacokinetic parameter estimates for abacavir following oral administration of single 100- to 1,200-mg doses to HIV-infected adults under fasting conditionsa

Mean AUC0–∞ values increased linearly with dose but not exactly proportionally to dose (slope ≠ 1) across all caplet doses (Table (Table2;2; Fig. Fig.2).2). On the basis of the power model, the mean slopes for the linear regression line of ln(AUC0–∞) versus ln(dose) and the associated 90% CIs were 1.47 (1.38 to 1.56) for doses of 100 to 1,200 mg and 1.11 (0.94 to 1.28) for doses of 600 to 1,200 mg. The inclusion of 1.0 in the 90% CIs for the 600- to 1,200-mg dose range indicates that AUC0–∞ is proportional to the dose in the higher dose range but not over the entire 100- to 1,200-mg dose range. When the LSM of each normalized dose was compared to the LSM of the 300-mg dose (the clinical dose being evaluated in current trials), the observed AUC0–∞ estimates for doses of 600 to 1,200 mg were greater than those predicted by dose proportionality (by 37 to 47%), as indicated by the LSM ratios (Table (Table3;3; Fig. Fig.2).2).

FIG. 2
(A) Mean ± standard deviation estimates of AUC0–∞ under fasting conditions versus dose. A linear but greater than dose-proportional relationship was noted between AUC0–∞ and dose. For example, a 4-fold increase ...
TABLE 3
Statistical analysis of pharmacokinetic parameter estimates of abacavir for escalating doses administered under fasting conditionsa

Mean Cmax values also increased linearly with dose but not exactly proportionally to dose (Table (Table2;2; Fig. 3). On the basis of the power model, the mean slope for the linear regression line of ln(Cmax) versus ln(dose) and 90% CIs were 1.18 (1.07 to 1.29) for doses of 100 to 1,200 mg and 1.04 (0.86 to 1.23) for doses of 600 to 1,200 mg. Thus, Cmax is proportional to dose over the higher dose range of 600 to 1,200 mg but not over the entire 100- to 1,200-mg dose range. When the LSM of each normalized dose was compared to the LSM of the 300-mg dose, the observed Cmax estimates for doses of from 600 to 1,200 mg were generally close to those predicted by dose proportionality, as indicated by the LSM ratios (Table (Table3;3; Fig. Fig.22).

Median Tmax values tended to be longer at the higher doses (by approximately 30 min) than at the lower doses, but they generally remained within the range of 1 to 2 h across treatments (Table (Table2).2). Mean t1/2β values tended to be slightly shorter for the 100- and 300-mg doses (0.9 to 1.2 h) than those for the higher doses (1.7 h) (Table (Table2).2). Generally, the terminal linear portion of the semilogarithmic plots at all dose levels were parallel within an individual subject, indicating linear kinetics (Fig. (Fig.11).

The bioavailability of the caplet formulation relative to that of the oral solution formulation, as assessed by the LSM ratios of AUC0–∞, was 96% (5.46 versus 5.67 μg · h/ml). Abacavir in solution was absorbed only slightly faster (by approximately 0.5 h) than the caplet formulation, as evidenced by a shorter median Tmax (0.6 versus 1.0 h), but this difference did not attain statistical significance (P = 0.06). The caplet and solution formulations did not differ with respect to Cmax (2.60 versus 2.52 μg/ml).

DISCUSSION

This is the first study to evaluate the safety and pharmacokinetics of abacavir in humans. The results of this study indicate that abacavir is well tolerated and rapidly absorbed following the administration of single oral doses ranging from 100 to 1,200 mg to HIV-infected adults. Single oral doses of abacavir of up to 1,200 mg were well tolerated by HIV-infected subjects. No significant changes in hematologic parameters and no significant laboratory abnormalities were observed throughout the study. This favorable safety profile of abacavir is well supported by preclinical toxicology studies with animals (2, 3, 6, 7).

The findings of this single-dose pharmacokinetic study indicate that abacavir reaches a maximum concentration rapidly (within 2 h), has adequate bioavailability (as indicated by concentrations in plasma), and has a relatively short t1/2β (<2 h). These values indicate that abacavir has absorption characteristics comparable to those of currently available RT inhibitors and a t1/2β that is similar to those of the other RT inhibitors except for 3TC (1, 4, 8, 9, 12).

The results of the statistical analysis across all five doses demonstrated the lack of strict dose proportionality for AUC0–∞ and Cmax, although the three highest doses were shown to be dose proportional. While the cause is unclear at this stage, the lack of proportionality in AUC0–∞ and Cmax over the lower dose range may be due to a possible first-pass effect which is saturated at higher doses, or it may be the result of an observational artifact associated with the assay of lower concentrations. Despite the overall lack of exact dose proportionality, abacavir dose is highly predictive of AUC0–∞ and Cmax due to the linear relationship. The deviation from dose proportionality over the entire dose range was not considered clinically significant for abacavir because only the 300-mg dose will be used clinically.

The intersubject variabilities in the pharmacokinetic parameter estimates were highest at the lower doses and tended to decrease with increasing dose. The variability at the lowest dose may be explained in part by higher assay variability at low drug concentrations. The variability in the pharmacokinetic data may be attributed to intersubject differences in the metabolism of abacavir or in the first-pass effect in the gastrointestinal tract or in the liver.

The bioavailability of the 100-mg caplet formulation relative to that of the solution was high (almost 100%), indicating that the disintegration and dissolution of abacavir from the caplet formulation were rapid and complete.

Administration of all single oral doses resulted in mean plasma abacavir concentrations that exceeded the IC50 for clinical HIV isolates (0.26 μM or 0.07 μg/ml) for almost 3 h (Fig. (Fig.1),1), and the mean plasma abacavir concentration for the 300-mg dose exceeded twice the IC50 (0.14 μg/ml) for over 6 h, i.e., over half the dosing interval for twice-daily administration. However, the in vivo antiviral effect is also dependent on factors such as distribution into target cells, kinetics of intracellular phosphorylation, and disposition of the active metabolite, carbocyclic guanosine triphosphate. It is noteworthy that the reported intracellular half-life of the active moiety of abacavir, carbocyclic guanosine triphosphate, was 3.3 h in CD4+ CEM cells (3), which is much longer than the plasma t1/2β observed in the current study (0.9 to 1.7 h). This difference in half-lives should sustain the intracellular concentrations of the active moiety. The longer intracellular half-life should also contribute to greater intracellular accumulation of the active moiety.

In summary, this study confirms the desirable pharmacokinetic properties and the favorable safety profiles of single oral doses of abacavir in HIV-infected individuals. The results of this study have supported the design of subsequent single- and multiple-dose studies with adults and children (with an oral solution) to evaluate the safety, antiviral activity, and pharmacokinetics of abacavir as monotherapy and in combination therapy with other antiretroviral agents for the treatment of HIV infection.

ACKNOWLEDGMENTS

This work was supported by a grant from Glaxo Wellcome Inc.

Special thanks are extended to William Mahony and Michael J. O’Mara for performing the bioanalytical studies.

REFERENCES

1. Child S, Montaner J, Tsoukas C, Fanning M, Le T, Wall R A, Ruedy J. Canadian multicenter azidothymidne trial: AZT pharmacokinetics. J Acquired Immune Defic Syndr. 1991;4:865–870. [PubMed]
2. Ching S V, Ayers K M, Dornsife R E, Grebe G L, Howard J L. Abstracts of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, D.C: American Society for Microbiology; 1994. Nonclinical toxicology and in vitro toxicity studies with the novel anti-HIV agent (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (1592U89) succinate, abstr. I88; p. 92.
3. Daluge S M, Good S S, Faletto M B, Miller W H, St. Clair M H, Boone L R, Tisdale M, Parry N R, Reardon J E, Dornsife R E, Averett D R, Krenitsky T A. 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity. Antimicrob Agents Chemother. 1997;41:1082–1093. [PMC free article] [PubMed]
4. Dudley M N, Graham K K, Kaul S, Geletko S, Dunkle L, Browne M, Mayer K. Pharmacokinetics of stavudine in patients with AIDS or AIDS-related complex. J Infect Dis. 1992;166:480–485. [PubMed]
5. Faletto M B, Miller W H, Garvey E P, St. Clair M H, Daluge S M, Good S S. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. Antimicrob Agents Chemother. 1997;41:1099–1107. [PMC free article] [PubMed]
6. Good S S, Owens B X, Faletto M B, Mahony W B, Domin B A. Abstracts of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, D.C: American Society for Microbiology; 1994. Disposition in monkeys and mice of (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (1592U89) succinate, a potent inhibitor of HIV, abstr. I86; p. 92.
7. Good S S, Daluge S M, Ching S V, Ayers M M, Mahony W B, Falletto M B, Domin B A, Owens B S, Dornsife R E, McDowell J A, LaFon S W, Symonds W T. 1592U89 succinate-preclinical toxicological and disposition studies and preliminary clinical pharmacokinetics. Antivir Res. 1995;26:A229.
8. Klecker R W, Jr, Collins J M, Yarchoan R C, Thomas R, McAtee N, Broder S, Myers C E. Pharmacokinetics of 2′,3′-dideoxycytidine in patients with AIDS and related disorders. J Clin Pharmacol. 1988;28:837–842. [PubMed]
9. Knupp C A, Shyu W C, Dolin R, Valentine F T, McLaren C, Martin R R, Pittman K A, Barbhaiya R H. Pharmacokinetics of didanosine in patients with acquired immunodeficiency syndrome or acquired immunodeficiency syndrome-related complex. Clin Pharmacol Ther. 1991;49:523–535. [PubMed]
10. McDowell J A, Symonds W T, Kumar P N, Sweet D E, Blum M R, LaFon S W. Abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, D.C: American Society for Microbiology; 1995. Initial phase-I study of anti-HIV agent 1592U89 in a single-dose escalation design including food effect and dosage form evaluation, abstr. I109; p. 224.
11. St. Clair M H, Millard J, Rooney J, Tisdale M, Parry N, Sadler B M, Blum M R, Painter G. In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents. Antivir Res. 1996;29:53–56. [PubMed]
12. Yuen G J, Morris D M, Mydlow P K, Haidar S, Hall S T, Hussey E K. Pharmacokinetics, absolute bioavailability, and absorption characteristics of lamivudine. J Clin Pharmacol. 1995;35:1174–1180. [PubMed]

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