M. Robert Blum

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.

Overview of acyclovir pharmacokinetic disposition in adults and children.

The metabolic disposition and pharmacokinetics of acyclovir have been studied as part of the clinical evaluation of the drug in humans. Data from 10 studies have been summarized and, when appropriate, pooled across studies for further analysis. The principal findings are as follows: Renal excretion is the major route of elimination of acyclovir and is dependent, in part, on active tubular secretion. Total body clearance (Cltot) and half-life are dependent on renal function as evaluated by estimated creatinine clearance (Clcr). Cltot is markedly reduced in the anuric patient. Plasma protein binding is low and drug interactions involving binding displacement are not anticipated. Acyclovir levels in cerebrospinal fluid are approximately 50 percent of corresponding plasma levels. Dose-independent pharmacokinetics is observed in the range of 0.5 to 15 mg/kg. Proportionality between dose and plasma levels is seen after single doses or at steady state after multiple dosing. Similar plasma levels are achieved in adults and pediatric patients (greater than 1 year) when equivalent doses are given based on body surface area. Intrasubject variability of acyclovir disposition is low. Much but not all intersubject variability in Cltot can be explained by differences in renal function. Dosage adjustment for various stages of renal impairment are proposed based on the observed relationship between Cltot and Clcr.

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.

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.

Alteration of zidovudine pharmacokinetics by probenecid in patients with AIDS or AIDS‐related complex

The anti–human immunodeficiency virus drug zidovudine is metabolized extensively in human beings to the 5′‐glucuronide (GAZT) and is cleared rapidly, resulting in a short half‐life and the need for frequent dosing. This study explores whether probenecid, which is also metabolized by glucuronidation, reduces zidovudine clearance when zidovudine is adminstered orally to patients with acquired immunodeficiency syndrome (AIDS) or AIDS‐related complex (ARC). The mean zidovudine plasma levels were significantly higher after concurrent administration of probenecid than in its absence, resulting in a twofold increase in the mean AUC, a corresponding decline in the apparent total clearance, and a prolongation in the mean half‐life. Similar alterations were observed in GAZT disposition. There was a marked reduction in the urinary excretion ratio of GAZT to zidovudine and a decline in the renal clearance of GAZT after probenecid coadministration. Probenecid inhibits zidovudine glucuronidation and renal excretion of GAZT.

Neonatal acyclovir pharmacokinetics in patients with herpes virus infections

A preliminary analysis is presented of the pharmacokinetics of acyclovir in neonatal patients with herpes simplex virus infections. Mean peak acyclovir levels (microM +/- SD) at 5, 10, and 15 mg/kg per dose were 30.0 +/- 9.9, 61.2 +/- 18.3, and 86.1 +/- 23.5, with corresponding mean trough levels (microM +/- SD) of 5.3 +/- 3.4, 10.1 +/- 8.4, and 13.8 +/- 11.1, respectively. The mean half-life (t 1/2 beta) of acyclovir was 3.78 +/- 1.21 hours. The mean percent urinary recovery of acyclovir (+/- SD) at each dosage level was similar, with an overall mean recovery of 65 percent. The mean acyclovir concentration in urine did not exceed the solubility of acyclovir in bladder urine (1,300 micrograms/ml). Generally, neonatal acyclovir pharmacokinetics was consistent with previous reports from studies of adults.

Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents: Pediatric AIDS clinical trials group protocol P1021

BACKGROUND. Compliance with complex antiretroviral therapy regimens is a problem for HIV-1–infected children and their families. Simple, safe, and effective regimens are important for long-term therapeutic success. METHODS. A novel, once-daily dosing regimen of 3 antiretroviral drugs, emtricitabine, didanosine, and efavirenz, was tested in 37 therapy-naive HIV-infected children and adolescents between 3 and 21 years of age (inclusive). Subjects were followed for ≥96 weeks on an intention-to-treat basis. Signs, symptoms, plasma HIV-1 RNA viral load, CD4 counts, and safety laboratories were followed regularly. End points were the proportion of subjects with plasma HIV <400 or 50 HIV copies per mL and safety and tolerability of the regimen. RESULTS. Thirty-seven subjects enrolled at 16 sites. Two subjects with rashes during the first 2 weeks of therapy were the only adverse events leading to study-drug discontinuation. Other early (before protocol-scheduled conclusion) study discontinuations included 3 viral failures on treatment and 5 patients who stopped therapy for apparently nonmedical reasons. Possible drug-related adverse events included 1 grade 4 low-glucose and 5 varied grade 3 events. There were no deaths. Virologic outcomes demonstrated that 32 (85%) of 37 subjects achieved viral suppression to <400 RNA copies per mL, and 26 (72%) of 37 subjects maintained sustained suppression at <50 copies per mL through week 96. The median baseline CD4 count was 310 per μL (17%), which increased at week 96 by a median of +329 cells per μL (by +18% CD4). Pharmacokinetic results were as predicted for emtricitabine, didanosine, and efavirenz capsules, whereas efavirenz concentrations in children receiving efavirenz oral solution were lower than anticipated, requiring a dose escalation after the planned assessment point. CONCLUSIONS. A once-daily regimen of emtricitabine, didanosine, and efavirenz proved to be safe and tolerable and demonstrated good immunologic and virologic efficacy in this 2-year study.

Pharmacokinetics of Tenofovir Disoproxil Fumarate and Ritonavir-Boosted Saquinavir Mesylate Administered Alone or in Combination at Steady State

ABSTRACT A phase I study was conducted to formally evaluate the steady-state pharmacokinetics (PK) of tenofovir disoproxil fumarate (TDF) and ritonavir (RTV)-boosted saquinavir mesylate (SQV) when coadministered in healthy volunteers. Forty subjects received multiple doses of TDF (300 mg, once daily) and SQV/RTV (1,000 mg/100 mg, twice daily) alone and together under steady-state conditions in an open-label, fixed sequence design. Blood samples for tenofovir (TFV) and SQV/RTV PK were drawn over respective 24- and 12-h dosing intervals, and drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Safety was assessed periodically by clinical and laboratory monitoring. Thirty-two subjects completed the study and were fully evaluable; three subjects discontinued participation in the study due to adverse events, three subjects withdrew for personal reasons, and two subjects withdrew because of inadequate venous access for blood sampling. Steady-state TFV PK were not significantly altered upon coadministration with SQV/RTV. Steady-state SQV (administered as SQV/RTV) AUCtau, Cmax, and Ctau increased 29, 22, and 47%, respectively, upon coadministration with TDF, and all subjects achieved a Ctau of >100 ng/ml. These modestly increased SQV exposures are not clinically meaningful given its clinical use with RTV already results in >10-fold-higher SQV levels. Steady-state RTV AUCtau and Cmax levels were not significantly altered, whereas Ctau was 23% higher upon coadministration of SQV/RTV and TDF. Thus, no clinically relevant interactions between TDF and RTV-boosted SQV were observed under conditions simulating clinical practice.

Cerebrospinal fluid levels of uric acid in dogs and the effect of allopurinol

Uric acid (UA) levels in cerebrospinal fluid (CSF) were measured in 15 dogs and the entrance and effect of allopurinol, a specific inhibitor of enzyme xanthine oxidase (XO), in brain were measured by sampling CSF in dogs. Allopurinol was administered intravenously 25 mg/kg every 6 h for 48 h. Drug level as well as UA level in plasma and CSF was measured by high-performance liquid chromatography. A significant concentration of allopurinol was achieved in CSF and a remarkable suppression of CSF UA level was observed at all time points measured. Decrease of UA in CSF level was more pronounced than in plasma, and was not considered secondary to suppression of systemic XO activity. Therefore the regimen employed was proven to be sufficient to suppress XO activity in the subarachnoid space, and drug concentration observed in CSF during this period (5 micrograms/ml) is considered to be in the therapeutic range.

Long-term safety and efficacy results of once-daily emtricitabine-based highly active antiretroviral therapy regimens in human immunodeficiency virus-infected pediatric subjects.

OBJECTIVES. The purpose of this work was to obtain long-term safety and efficacy data for antiretroviral regimens containing emtricitabine in HIV-infected pediatric subjects and confirm that a pediatric dose of 6 mg/kg once daily would provide steady-state emtricitabine concentrations comparable to those observed in adults given 200 mg of emtricitabine once daily. PATIENTS AND METHODS. HIV-infected subjects between 3 months and 16 years of age were enrolled, including 71 antiretroviral-naïve subjects and 45 antiretroviral-experienced subjects. Naive subjects received emtricitabine plus stavudine plus lopinavir or ritonavir. Experienced subjects replaced the lamivudine in their existing regimens with emtricitabine. Tolerance, safety, disease progression, and virologic and immunologic responses were evaluated. RESULTS. The Kaplan-Meier probability of persistent virologic response in the intent-to-treat population through week 164 at ≤400 copies per mL and ≤50 copies per mL was 74% and 62%, respectively. Three subjects (3%) discontinued the study for adverse events, 8 (7%) for virologic failure, and 1 died through a median follow-up of 164 weeks. The annualized incidence rate of grade 3 to 4 adverse events and grade 3 to 4 laboratory abnormalities was 6% and 3%, respectively. The annualized incidence rate of serious adverse events was 9%, with 1% attributed as related to emtricitabine. Genotypic analysis showed the emergence of the M184V mutation in 4 of the 15 subjects who experienced virologic failure through week 164. Pharmacokinetic evaluation demonstrated plasma drug exposures in these children comparable to adults receiving the approved dose of 200 mg once daily. CONCLUSIONS. These results demonstrate the safety and efficacy of emtricitabine in pediatric patients. They also support that the safety and efficacy profile of emtricitabine in children is similar to that demonstrated in adults.