Stephen Weller

Pharmacokinetics of the acyclovir pro‐drug valaciclovir after escalating single‐and multiple‐dose administration to normal volunteers

The pharmacokinetics and safety of the L‐valyl ester pro‐drug of acyclovir, valaciclovir (256U87), were investigated in two phase I, placebo‐controlled trials in normal volunteers. These included a single‐dose study with doses from 100 to 1000 mg (single cohort) and a multiple‐dose investigation with doses from 250 to 2000 mg (five separate cohorts). In each cohort, eight subjects received valaciclovir and four subjects received placebo. Pharmacokinetic findings for valaciclovir and acyclovir were consistent in the two studies. Valaciclovir was rapidly and extensively converted to acyclovir, resulting in significantly greater acyclovir bioavailability (~ threefold to fivefold) compared with that historically observed with high‐dose (800 mg) oral acyclovir. At the higher valaciclovir doses, acyclovir maximum concentration and daily area under the concentration‐time curve approximated those obtained with intravenous acyclovir. The favorable safety profile and enhanced acyclovir bioavailability from valaciclovir administration has prompted additional clinical evaluations for zoster and herpes simplex virus treatment, as well as cytomegalovirus suppression in immunocompromised patients.

The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: Phase I Acquired Immunodeficiency Syndrome Clinical Trials Group study (protocol 082)

OBJECTIVES: We measured the pharmacokinetics and safety of zidovudine in pregnant women infected with human immunodeficiency virus and their offspring. STUDY DESIGN: Asymptomatic human immunodeficiency virus-infected women with uncomplicated singleton gestations (28 to 36 weeks) underwent parenteral and oral zidovudine treatment during pregnancy and labor. Maternal and neonatal drug levels were measured at delivery and sequentially for 48 hours. Infants were followed up for 18 months. RESULTS: The total body clearance (26.3 ± 10.1 ml/min/kg), mean terminal elimination phase zidovudine half-life (1.3 ± 0.2 hours), and urinary zidovudine recovery were similar to values in nonpregnant adults. Essentially equivalent zidovudine levels in the mother and neonate at delivery implied little, if any, fetal zidovudine metabolism. The half-life of zidovudine in the neonates was tenfold that of the mother. No significant adverse effects were noted in the infant at birth or on follow-up. CONCLUSIONS: In both mothers and infants the drug appeared safe and well tolerated with no significant hematologic abnormalities.

Combination therapy with zidovudine and didanosine compared with zidovudine alone in HIV-1 infection

Zidovudine (AZT, Retrovir) delays progression of human immunodeficiency virus type 1 (HIV-1) infection and prolongs survival in persons with advanced HIV-1 disease [1-5]. However, with prolonged therapy, clinical disease progresses, CD4+ cell counts decrease, and variants of HIV-1 occur that have decreased in vitro susceptibility to zidovudine [6-12]. Didanosine (Videx), another nucleoside analogue that inhibits the reverse transcriptase of HIV-1, increases CD4+ cell counts and delays progression of HIV-1 disease among patients who previously received zidovudine therapy [13-16]. The combination of zidovudine and didanosine has additive to synergistic inhibitory activity against HIV-1 in vitro [17, 18] and is being used clinically, because both agents are licensed and available. We did a clinical trial to characterize the safety and efficacy of a range of doses using combination zidovudine and didanosine therapy compared with zidovudine therapy alone. We found that this combination therapy is well tolerated and is associated with enhanced in vivo activity as shown by higher and more prolonged increases of CD4+ cell counts, with more frequent decreases in plasma HIV-1 RNA titers, and with more stable hematologic measurements than zidovudine therapy alone. Table 1. Pretreatment Characteristics of Patients in the Six Treatment Groups Methods Patients Between February 1990 and August 1991, 69 patients were enrolled in the study: 30 at University of Washington, 14 at University of Miami, 14 at New England Medical Center and Tufts University, and 11 at University of California, San Francisco. Patients had HIV-1 infection, CD4+ cell counts fewer than 400/mm3, fewer than 121 days of previous zidovudine therapy (Retrovir; Burroughs Wellcome Company, Research Triangle Park, North Carolina), and no previous didanosine therapy (Videx; Bristol Laboratories, Princeton, New Jersey). Patients also had granulocyte counts of 1200 cells/mm3 or more, hemoglobin levels greater than 90 g/L, platelet counts greater than 90 000/mm3, creatinine levels less than 1.5 times the upper limit of normal, and aspartate aminotransferase levels less than 5 times the upper limit of normal. Patients were excluded if they had visceral or progressive Kaposi sarcoma; more than four stools per day for 4 weeks; opportunistic infections requiring maintenance therapy; a history of pancreatitis, seizures, peripheral neuropathy, or zidovudine or didanosine intolerance; were pregnant or nursing; were taking experimental medications; or required chronic acyclovir therapy. Study Design The study was an open-label, partially randomized study of five different combination regimens of zidovudine and didanosine and one dosage regimen of zidovudine alone (Figure 1). Zidovudine was given as capsules three times per day. Didanosine was given twice daily as sachets containing a citrate/phosphate buffer with a neutralizing capacity of 30 to 40 mEq/dose. Because of initial concerns about the safety of this combination, enrollment was required in the lower dose groups (groups 1, 2, and 3) before enrollment in groups 4 and 5. In March 1991, after enrollment was completed in groups 1 to 5, the protocol was modified to enroll consecutively identified eligible patients in the zidovudine-alone regimen (group 6), to permit a comparison with standard therapy. Because standard zidovudine therapy in the United States at the time this trial was done was 500 to 600 mg daily, the groups that included zidovudine at 600 mg daily (groups 3, 5, and 6) were planned to have larger enrollment than the other groups. Treatment duration was 24 weeks. Patients were replaced if they discontinued treatment permanently before week six for reasons other than toxicity. Figure 1. Outline of the study design. Patient Evaluation The study protocol was approved by institutional review boards of participating institutions, and patients gave written informed consent. Patients had a standardized clinical and laboratory evaluation at enrollment and had weekly follow-up visits for 4 weeks and then every 2 weeks. Symptoms and signs were assessed at each visit and were graded as absent or within normal limits, or as mild, moderate, severe, or life-threatening severity. Patients at the University of Washington in groups 3 (n = 9) and 5 (n = 6) had blood samples collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours for pharmacokinetic assays, after a single 200-mg zidovudine dose, 2 days before starting study drugs, and after a single 167- or 250-mg didanosine dose on the day before starting combination therapy. In addition, 26 patients in groups 3 and 5 had plasma collected on a similar schedule during weeks 2 (n = 26) and 12 (n = 23). Doses of study drugs were modified if patients had moderate peripheral neuropathy or certain severe toxicities. Study drugs were permanently discontinued for severe or life-threatening toxicities. Laboratory Measurements CD4+ and CD8+ cells from peripheral blood were enumerated using monoclonal antibodies and flow cytometry [19]. Sera from each patient, frozen at 30C, were assayed simultaneously for HIV-1 p24 antigen by an enzyme-linked immunosorbent assay (Abbott Laboratories, North Chicago, Illinois). A positive result for HIV-1 was defined as 12 pg/mL using an HIV-1 p24 antigen reference standard supplied by the AIDS Clinical Trials Group Virology Reference Laboratory. Sera from patients enrolled at the University of Washington were also assayed for immune-complex dissociated-HIV p24 antigen (Abbott Laboratories). Plasma from patients enrolled at the University of Washington, stored at 70C, was assayed for HIV-1 RNA by a semiquantitative polymerase chain reaction technique, as previously described [20]. All assays were done in duplicate on coded samples, and the semiquantitative assessment of the polymerase chain reaction-signal strength was graded using scanning densitometry without knowledge of any clinical data or treatment group. Zidovudine concentrations in plasma were determined by radioimmunoassay [21]. Plasma didanosine concentrations were analyzed by high-performance liquid chromatography [22]. Data Analysis Comparisons among groups were made using chi-square analysis or the Fisher exact test for discrete variables and using the Wilcoxon Mann-Whitney test and Kruskal-Wallis test among three or more groups for continuous variables. All P values were two-tailed. To evaluate the effect of therapy for sequentially monitored variables, area-under-the-curve (AUC) analyses were done based on absolute change from pretreatment or time-averaged absolute change from pretreatment values. The baseline CD4+ cell count was an average of two pretreatment counts for each patient. The AUC for CD4+ cell counts was calculated by multiplying the average CD4+ cell count between two successive time points by the time elapsed between those time points, summing these areas for the study period, and dividing the result by the duration of the study period. This AUC was strongly related to the pretreatment CD4+ cell count. Analysis of covariance, adjusting for the initial CD4+ cell count, was used to examine the relation between the treatment group and the AUC. Residuals from the model were analyzed, and no pattern was discernible, suggesting the model was appropriate. Area-under-the-curve analysis, based on absolute CD4+ cell changes from pretreatment values, was used to compare these areas across groups using nonparametric statistics. The proportion of patients with an increase in absolute CD4+ cells of 50 and 100 cells/mm3, on two consecutive measurements above the pretreatment value, was evaluated using contingency tables. The duration of response was defined as the time to two consecutive counts at or below baseline and was analyzed using Kaplan-Meier survival techniques. Pharmacokinetic parameter estimates were calculated by standard methods and included the peak concentration (Cmax), the time to peak concentration (Tmax), the elimination half-life (t1/2), the AUC, and the apparent oral clearance. The evaluation of a pharmacokinetic drug interaction between zidovudine and didanosine was done by paired t-test analysis of parameter estimates obtained for those patients in groups 3 and 5 who received single doses of zidovudine alone (day 2) and didanosine alone (day 1) followed by coadministration of both compounds with pharmacokinetic evaluations in weeks 2 and 12. Parameter estimates were considered statistically different for P values less than 0.05. Results Study Patients Sixty-seven (97%) patients were men; 61 (88%) were white, 2 (3%) were black, and 6 (9%) were of other races. The mean age (SD) was 34 6 years. Fifty-four (78%) were homosexual or bisexual men, 8 (12%) were homosexual or bisexual men who also used injection drugs, 2 (3%) were injection drug users, 3 (4%) had heterosexually acquired HIV-1, 1 (1%) had hemophilia, and 1 (1%) had unknown risk behavior for HIV. Thirty-eight (55%) patients were asymptomatic, 22 (32%) had constitutional symptoms, and 9 (13%) had the acquired immunodeficiency syndrome (AIDS). The median pretreatment CD4+ cell count was 259 cells/mm3, and the median Karnofsky performance score was 100. No statistical differences were seen in demographic, clinical, or laboratory characteristics among the six dosing groups, except for the expected difference in frequency of detectable HIV-1 p24 antigen (Table 1). The median HIV-1 p24 antigen level for patients in group 1 was 140 pg/mL (range, 17 to 282 pg/mL). Thirty-one patients had taken previous zidovudine therapy; the mean duration of therapy (SD) was 65 days ( 36 days). Fifty-eight (84%) patients completed 24 weeks of study treatment and 11 (16%) discontinued study treatment, 5 before week 6. Pretreatment characteristics of patients who discontinued treatment were similar to those who completed therapy. The reasons for study medication discontinuation were toxicity (3 patients), administrative reasons (4

Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus

This study evaluated the safety, tolerability, and pharmacokinetics of zidovudine administered intravenously and orally to infants born to women infected with the human immunodeficiency virus. Thirty-two symptom-free infants were enrolled before 3 months of age. The pharmacokinetics of zidovudine were evaluated in each infant after single intravenously and orally administered doses of zidovudine on consecutive days, and during long-term oral administration of the drug for 4 to 6 weeks. As new patients were enrolled, doses of zidovudine were progressively increased from 2 to 4 mg/kg. Therapy was continued for up to 12 months in 7 of the infants proved to be infected with human immunodeficiency virus. Zidovudine was generally well tolerated; 20 children (62.5%) had anemia (hemoglobin level < 10.0 gm/dl) during therapy and 9 (28.1%) had neutropenia (neutrophil count < or = 750 cells/mm3); these hematologic abnormalities usually resolved spontaneously. The total body clearance of zidovudine increased significantly with age, from an average of 10.9 ml/min per kilogram in infants < or = 14 days of age to 19.0 ml/min per kilogram in older infants (p < 0.0001). Concurrently, there was a significant decrease in serum half-life from 3.12 hours in infants < or = 14 days to 1.87 hours in older infants (p = 0.0002). Oral absorption was satisfactory and bioavailability decreased significantly with age, from 89% in infants < or = 14 days to 61% in those > 14 days of age (p = 0.0002). Plasma concentrations of zidovudine were calculated to be in excess of 1 mumol/L (0.267 micrograms/ml) for 4.12 +/- 1.86 hours and 2.25 +/- 0.78 hours after oral doses of 2 mg/kg in infants younger than 2 weeks and 3 mg/kg in older infants, respectively. We conclude that zidovudine administered at oral doses of 2 mg/kg every 6 hours to infants aged less than 2 weeks and 3 mg/kg every 6 hours to infants older than 2 weeks resulted in plasma concentrations that are considered virustatic against human immunodeficiency virus. Zidovudine was well tolerated by infants at these doses.

Population Pharmacokinetics and Pharmacodynamic Modeling of Abacavir (1592U89) from a Dose-Ranging, Double-Blind, Randomized Monotherapy Trial with Human Immunodeficiency Virus-Infected Subjects

ABSTRACT Abacavir (formerly 1592U89) is a carbocyclic nucleoside analog with potent anti-human immunodeficiency virus (anti-HIV) activity when administered alone or in combination with other antiretroviral agents. The population pharmacokinetics and pharmacodynamics of abacavir were investigated in 41 HIV type 1 (HIV-1)-infected, antiretroviral naive adults with baseline CD4+ cell counts of ≥100/mm3 and plasma HIV-1 RNA levels of >30,000 copies/ml. Data for analysis were obtained from patients who received randomized, blinded monotherapy with abacavir at 100, 300, or 600 mg twice-daily (BID) for up to 12 weeks. Plasma abacavir concentrations from sparse sampling were analyzed by standard population pharmacokinetic methods, and the effects of dose, combination therapy, gender, weight, and age on parameter estimates were investigated. Bayesian pharmacokinetic parameter estimates were calculated to determine the peak concentration of abacavir in plasma (Cmax) and the area under the concentration-time curve from time zero to infinity (AUC0–∞) for individual subjects. The pharmacokinetics of abacavir were dose proportional over the 100- to 600-mg dose range and were unaffected by any covariates. No significant correlations were observed between the incidence of the five most common adverse events (headache, nausea, diarrhea, vomiting, and malaise or fatigue) and AUC0–∞. A significant correlation was observed betweenCmax and nausea by categorical analysis (P = 0.019), but this was of borderline significance by logistic regression (odds ratio, 1.45; 95% confidence interval, 0.95 to 2.32). The log10 time-averaged AUC0–∞ minus baseline (AAUCMB) values for HIV-1 RNA and CD4+ cell count correlated significantly withCmax and AUC0–∞, but with better model fits for AUC0–∞. The increase in AAUCMB values for CD4+ cell count plateaued early for drug exposures that were associated with little change in AAUCMB values for plasma HIV-1 RNA. There was less than a 0.4 log10 difference over 12 weeks in the HIV-1 RNA levels with the doubling of the abacavir AUC0–∞ from 300 to 600 mg BID dosing. In conclusion, pharmacodynamic modeling supports the selection of abacavir 300 mg twice-daily dosing.

Pharmacokinetics of acyclovir suspension in infants and children.

Eighteen children from 3 weeks to 6.9 years of age were given an oral acyclovir suspension for herpes simplex or varicella-zoster virus infections. Thirteen patients who were 6 months to 6.9 years old received 600 mg/m2 per dose, and three infants and two children less than 2 years old were given 300 mg/m2 per dose. The drug was given four times a day, except to one infant who was treated with three doses a day. Among the 13 children who received the 600-mg/m2 dose, the maximum concentration in plasma (Cmax) was 0.99 +/- 0.38 microgram/ml (mean +/- standard deviation), the time to maximum concentration (Tmax) was 3.0 +/- 0.86 h, the area under the curve (AUC) was 5.56 +/- 2.17 micrograms.h/ml, and the elimination half-life (t1/2) was 2.59 +/- 0.78 h. The three infants less than 2 months of age who received the 300-mg/m2 dose had a Cmax of 1.88 +/- 1.11 micrograms/ml, a Tmax of 4.10 +/- 0.48 h, an AUC of 6.54 +/- 4.32 micrograms.h/ml, and a t1/2 of 3.26 +/- 0.33 h. The acyclovir suspension was well tolerated by young children. No adverse effects requiring discontinuation of the drug occurred.

Bioequivalence of a dolutegravir, abacavir, and lamivudine fixed-dose combination tablet and the effect of food.

Background:The integrase inhibitor dolutegravir and nucleoside analogues abacavir and lamivudine are once-daily treatment options for HIV. This study (NCT01622790) evaluated, first, the bioequivalence (BE) of a fixed-dose combination (FDC) tablet containing dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (dolutegravir/abacavir/lamivudine FDC) vs coadministered dolutegravir 50 mg and abacavir/lamivudine combination tablets (Epzicom) and, second, the effect of food on the dolutegravir/abacavir/lamivudine FDC tablet. Methods:Study part A (66 healthy subjects) was a single-dose, open-label, randomized, 2-period crossover study to evaluate the BE of the dolutegravir/abacavir/lamivudine FDC tablet and dolutegravir + abacavir/lamivudine tablets in the fasted state. In study part B, 12 subjects from part A received the dolutegravir/abacavir/lamivudine FDC tablet with a high-fat meal. BE and food effect were assessed by analysis of variance to determine the ratio of geometric least squares means and associated 90% confidence intervals for key pharmacokinetic parameters for each of dolutegravir, abacavir, and lamivudine. Results:Sixty-two subjects completed part A. The dolutegravir/abacavir/lamivudine tablet was bioequivalent to the dolutegravir + abacavir/lamivudine tablets; 90% confidence intervals for the geometric least squares mean ratios fell within the 0.8–1.25 BE criteria. The effect of food on the dolutegravir/abacavir/lamivudine FDC tablet was similar to previous food effects observed with the separate formulations. The safety profile was comparable between treatments, with no observed serious or grade 3/4 adverse events. Conclusions:The BE of the dolutegravir/abacavir/lamivudine FDC tablet was demonstrated; it may be administered without regard to meals.

Pharmacokinetics of Acyclovir and Its Metabolites in Cerebrospinal Fluid and Systemic Circulation after Administration of High-Dose Valacyclovir in Subjects with Normal and Impaired Renal Function

ABSTRACT Valacyclovir, the l-valyl ester prodrug of acyclovir (ACV), is widely prescribed to treat infections caused by varicella-zoster virus or herpes simplex virus. Rarely, treatment is complicated by reversible neuropsychiatric symptoms. By mechanisms not fully understood, this occurs more frequently in the setting of renal impairment. We characterized the steady-state pharmacokinetics of ACV and its metabolites 9-[(carboxymethoxy)methyl]guanine (CMMG) and 8-hydroxy-acyclovir (8-OH-ACV) in cerebrospinal fluid (CSF) and the systemic circulation. We administered multiple doses of high-dose valacyclovir to 6 subjects with normal renal function and 3 subjects with chronic renal impairment (creatinine clearance [CrCl], ∼15 to 30 ml/min). Dosages were 2,000 mg every 6 h and 1,500 mg every 12 h, respectively. Indwelling intrathecal catheters allowed serial CSF sampling throughout the dosing interval. The average steady-state concentrations of acyclovir, CMMG, and 8-OH-ACV were greater in both the systemic circulation and the CSF among subjects with impaired renal function than among subjects with normal renal function. However, the CSF penetration of each analyte, reflected by the CSF-to-plasma area under the concentration-time curve over the 6- or 12-h dosing interval (AUCτ) ratio, did not differ based on renal function. Renal impairment does not alter the propensity for ACV or its metabolites to distribute to the CSF, but the higher concentrations in the systemic circulation, as a result of reduced elimination, are associated with proportionally higher concentrations in CSF.

Pharmacokinetics and Safety of Extemporaneously Compounded Valacyclovir Oral Suspension in Pediatric Patients from 1 Month through 11 Years of Age

BACKGROUND Valacyclovir provides enhanced acyclovir bioavailability in adults, but limited data are available in children. METHODS Children 1 month through 5 years of age with or at risk for herpesvirus infection received a single 25 mg/kg dose of extemporaneously compounded valacyclovir oral suspension (n = 57), whereas children 1 through 11 years of age received 10 mg/kg valacyclovir oral suspension twice daily for 3-5 days (herpes simplex virus infection) (n = 28) or 20 mg/kg 3 times daily for 5 days (varicella-zoster virus infection) (n = 27). Blood samples for pharmacokinetic analysis were collected during the 6 h after the first dose. Safety was monitored throughout the studies. RESULTS Dose proportionality in the maximum observed concentration (C(max)) of acyclovir and the area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)) existed across the 10 to 20 mg/kg valacyclovir dose range. For children 2 through 5 years of age, an increase in dose from 20 to 25 mg/kg resulted in near doubling of the C(max) and AUC(0-infinity). Among infants 1 through 2 months of age receiving 25 mg/kg, the mean AUC(0-infinity) and C(max) were higher ( approximately 60% and 30%, respectively) than those among older infants and children receiving the same dose. Valacyclovir oral suspension was well tolerated. No clinically significant trends were noted in clinical chemical, hematologic, or urinalysis values from screening to follow-up. CONCLUSIONS Among children 3 months through 11 years of age, the 20 mg/kg dose of this formulation of valacyclovir oral suspension produces favorable acyclovir blood concentrations and is well tolerated. A dosing recommendation cannot be made for infants <3 months of age because of decreased clearance in this age group. Trial registration. ClinicalTrials.gov identifier: NCT00297206 .

An Investigation of the Steady-State Pharmacokinetics of Oral Valacyclovir in Immunocompromised Children

Valacyclovir was administered to 28 immunocompromised children (ages 5-12 years) to obtain preliminary pharmacokinetic and safety information. Patients were randomized to valacyclovir regimens of 250 mg (9.4-13.3 mg/kg) or 500 mg (13.9-27.0 mg/kg) twice daily or 500 mg (13.2-21.7 mg/kg) 3 times a day. Acyclovir pharmacokinetics were evaluated at steady state. Valacyclovir was rapidly absorbed and converted to acyclovir. Mean (+/-SD) acyclovir peak concentrations from 250 mg and 500 mg valacyclovir were 4.11+/-1.41 and 5.19+/-1.96 microg/mL, respectively. Corresponding single dose area-under-curve values were 12.14+/-6.60 and 14.49+/-4.69h microg/mL. By using historical data for intravenous acyclovir as reference, the overall estimate of acyclovir bioavailability from valacyclovir was 48%, 2- to 4-fold greater than for oral acyclovir. In general, adverse events were not attributable to valacyclovir and were consistent with disease-related expectations and concomitant therapies. Dosage options for using valacyclovir in children are discussed.