An oral human drug absorption study to assess the impact of site of delivery on the bioavailability of bevirimat.

Bevirimat is a first in class, orally active, potent and selective inhibitor of HIV-1. It may have utility for the treatment of HIV-1-infected patients who are failing current regimens because of the development of drug resistance. In earlier studies in HIV-1-infected patients, an immediate-release tablet formulation exhibited a relative bioavailability (F(rel)) of 50% or greater and a higher intersubject variability than an oral solution. The purpose of this study was to determine whether this pharmacokinetic profile is attributable to a narrow permeability-dependent absorption window within the gastrointestinal tract. Three groups of subjects completed an open-label, 2-way crossover, randomized pharmacoscintigraphic study. Subjects received a 25-mg bevirimat oral immediate-release solution plus 25 mg bevirimat solution delivered to the proximal small bowel, distal small bowel, or colon via the Enterion capsule. The results indicate that the permeability of bevirimat throughout the small intestine was excellent and suggest that the variability observed for the immediate release tablet was not related to the presence of an absorption window in the small intestine.

Pharmacokinetic properties and tolerability of bevirimat and atazanavir in healthy volunteers: an open-label, parallel-group study.

BACKGROUND: Bevirimat, an inhibitor of HIV-1 maturation, is currently in clinical development for the treatment of HIV-1 infection. It undergoes glucuronidation via uridine diphosphate glucuronosyltransferases (UGTs). The protease inhibitor atazanavir is a potent inhibitor of UGT1A1. Because of this inhibition, high atazanavir plasma levels are associated with increases in plasma bilirubin. OBJECTIVES: The purposes of this study were to assess the pharmacokinetic (PK) properties and tolerability profiles of bevirimat administered as monotherapy and in combination with atazanavir. METHODS: This was an open-label, parallel-group study in healthy volunteers. Nonsmoking men and women aged 18 to 60 years were eligible for inclusion in the study. After being stratified in a 1:1 ratio by sex, subjects were randomly assigned to 1 of 2 groups to receive bevirimat 200 mg/d for 14 days or atazanavir 400 mg/d on days 1 through 21 and bevirimat 200 mg/d on days 8 through 21. Bevirimat PK properties were assessed on day 14 in the monotherapy group and on day 21 in the combination group. Atazanivir PK properties were assessed on days 7 and 21 in the combination group. Serum bilirubin was assessed daily. Tolerability was assessed by monitoring of adverse events using physical examination and clinical laboratory evaluation, including recording of vital signs and electrocardiography throughout the study. RESULTS: A total of 48 healthy volunteers (24 men, 24 women; mean age, 33 years; mean weight, 83.6 kg; mean body mass index, 27.8 kg/m(2)) were included in the study. There were no significant between-group effects on the PK properties with respect to geometric least squares mean ratios of C(max) and AUC(0-tau) (95.9 [90% CI, 84.5-108.8] and 92.0 [90% CI, 80.5- 105.2], bevirimat monotherapy vs bevirimat + atazanivir, respectively; and 93.9 [90% CI, 82.3-107.1 and 94.1 [90% CI, 78.2-113.1], atazanivir monotherapy vs bevirimat + atazanivir, respectively). Bevirimat was not associated with any significant changes from baseline in serum bilirubin concentrations, whereas 7-day atazanavir monotherapy was associated with a appromixately 5-fold increase. Coadministration was not associated with significant bilirubin concentration elevations compared with the administration of atazanavir alone. Dosing was discontinued in 4 subjects (atazanavir-induced hyperbilirubinemia, 3; atazanavir-induced rash, 1). In addition, 17 subjects (35.4%) experienced treatment-emergent adverse events including: ocular icterus, 5; headache, 5; unconjugated blood bilirubin increases, 4; diarrhea, 3; upper respiratory tract infection, 3; and yellow skin, 3. CONCLUSIONS: In this study, there were no significant differences in PK properties in atazanavir or bevirimat administered as monotherapy or in combination in this small, select group of healthy volunteers. The coadministration of bevirimat and atazanavir was reasonably well tolerated. Bevirimat did not significantly increase serum bilirubin concentrations and had no significant effect on atazanavir-induced hyperbilirubinemia, potentially providing a further option in the management of HIV-1 infection following evaluation in HIV-infected patients.

Phase I and II study of the safety, virologic effect, and pharmacokinetics/pharmacodynamics of single-dose 3-o-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus infection.

Bevirimat [3-O-(3',3'-dimethylsuccinyl)betulinic acid] is the first in a new class of anti-human immunodeficiency virus (HIV) drugs that inhibit viral maturation by specifically blocking cleavage of the Gag capsid (CA) precursor, CA-SP1, to mature CA protein, resulting in defective core condensation and release of immature noninfectious virions. Four cohorts of six HIV-infected adults, with CD4 counts of >200 and plasma viral loads of 5,000 to 250,000 transcripts/ml and not currently receiving antiretroviral therapy, were randomized to receive a single oral dose of placebo, 75, 150, or 250 mg of bevirimat. Thirty blood samples for drug concentrations and 20 HIV RNA measures were collected from each subject over a 20-day period. Candidate pharmacokinetic/pharmacodynamic models were fit to individual subjects by maximum likelihood followed by Bayesian estimation; model discrimination was by corrected Akaike's Information Criterion. The bevirimat pharmacokinetics was well described by an oral two-compartment linear model (r(2), 0.98), with a mean (percent coefficient of variation) half-life of 60.3 (13.6) h and apparent oral clearance of bevirimat from the plasma compartment of 0.17 (18) liters/h. HIV RNA was modeled as being produced in infected CD4 cells, with bevirimat inhibiting infection of new CD4 cells thru a Hill-type function (r(2), 0.87). Single oral doses of bevirimat were well tolerated and demonstrated a dose-dependent reduction in viral load. The average maximum reduction from baseline following the 150- and 250-mg doses was greater than 0.45 log(10), with individual patients having reductions of greater than 0.7 log(10). No bevirimat resistance mutations were detected during the course of the study.

Multiple-dose pharmacokinetics and safety of bevirimat, a novel inhibitor of HIV maturation, in healthy volunteers.

BACKGROUND AND OBJECTIVE: Bevirimat [3-O-(3',3'-dimethylsuccinyl)-betulinic acid] is a novel inhibitor of HIV-1 maturation. This study was performed to investigate the pharmacokinetics and safety of bevirimat during repeated dosing in healthy volunteers. SUBJECTS AND METHODS: The study was a 10-day, randomised, double-blind, placebo-controlled, dose escalation study. A total of 48 healthy male volunteers, aged 19-54 years, took part in the study. Treatment was administered for 10 days in six escalating dose cohorts (n = 8 in each cohort; 6 bevirimat, 2 placebo). The doses of bevirimat given in each successive cohort were 25 mg, 50 mg, 75 mg (with 150 mg loading dose), 100 mg, 150 mg and 200mg. Safety follow-up was performed 28 days after the first dose. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Plasma bevirimat levels were measured from blood samples collected pre-dose on days 1-10 and then at approximately 48-hour intervals until 21 days after dosing started. On days 1 and 10, further blood samples were obtained at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours after dosing. Urine samples were collected in the morning on days 1, 5 and 11 and at the end of the study for the measurement of cortisol and 6beta-hydroxycortisol. The pharmacokinetic parameters of bevirimat were estimated using non-compartmental methods. MAIN OUTCOME MEASURE: Dose proportionality of exposure to bevirimat, assessed by the maximum plasma concentration and the area under the plasma concentration-time curve. RESULTS: The mean terminal elimination half-life of bevirimat ranged from 56.3 to 69.5 hours, and the mean clearance ranged from 173.9 to 185.8 mL/hour. Bevirimat showed approximately 4-fold greater accumulation on day 10 compared with day 1, and the degree of accumulation was similar with all doses. Maximum plasma concentrations ranged from 8 to 58 microg/mL at day 10. Testing for dose-proportionality showed that exposure to bevirimat was proportional to the dose, both after a single dose and after repeat dosing for 10 days. Measurement of the urinary 6beta-hydroxycortisol/cortisol ratio indicated that bevirimat did not affect cytochrome P450 3A activity. Repeated dosing with bevirimat for 10 days was well tolerated. There was no increase in adverse events observed for bevirimat compared with placebo, and no serious adverse events occurred. No clinically relevant changes in vital signs, physical examination or clinical laboratory evaluations were observed. CONCLUSIONS: Bevirimat shows dose-proportional pharmacokinetics during repeated dosing for 10 days. Its accumulation is approximately 4-fold greater on day 10 compared with day 1. Repeated dosing with bevirimat is well tolerated. These properties make bevirimat potentially suitable for inclusion in highly active antiretroviral therapy regimens.

Safety and pharmacokinetics of Bevirimat (PA-457), a novel inhibitor of human immunodeficiency virus maturation, in healthy volunteers.

Bevirimat (BVM; formerly known as PA-457) is a novel inhibitor of human immunodeficiency virus (HIV) maturation that is being developed for the treatment of HIV infection. The pharmacokinetics of this agent in healthy male volunteers were studied in a randomized, double-blind study in which the participants received single oral doses of placebo (n = 8) or escalating doses of BVM at 25, 50, 100, or 250 mg (n = 6 per dose); escalation was performed only after the pharmacokinetics and safety of the preceding dose had been evaluated. Plasma was collected over 480 h after dosing and urine was collected over 48 h after dosing for determination of the values of pharmacokinetic parameters. BVM was well absorbed after oral administration, with peak plasma concentrations being achieved 1 to 3 h after dosing. The half-life was 60 to 80 h. The exposure assessed by determination of the peak concentration and the area under the concentration-time curve was dose proportional. Single oral doses of BVM were well tolerated: there were no dose-limiting toxicities, and no serious adverse events were reported. These findings suggest that that BVM offers a favorable pharmacokinetic profile, with predictable pharmacokinetics following the oral administration of single doses. The long half-life of BVM may facilitate once-daily dosing.