Pharmacokinetics and safety study of posaconazole intravenous solution administered peripherally to healthy subjects.

This study evaluated the safety, tolerability, and pharmacokinetics of a posaconazole i.v. (intravenous) solution. This was a single-center, 2-part, randomized, rising single- and multiple-dose study in healthy adults. In part 1, subjects received 0 (vehicle), 50, 100, 200, 250, or 300 mg posaconazole in a single dose i.v. by 30-min peripheral infusion (6 cohorts of 12 subjects each [9 active and 3 placebo], making a total of 72 subjects). Blood samples were collected until 168 h postdose. In part 2, subjects were to receive 2 peripheral infusions at a 12-h interval on day 1 followed by once-daily infusion for 9 days. However, part 2 was terminated early because of high rates of infusion site reactions with multiple dosing at the same infusion site. The pharmacokinetics results for part 1 (n=45 subjects) showed that the mean posaconazole exposure (area under the concentration-time curve from time zero to infinity [AUC0-∞]) ranged from 4,890 to 46,400 ng · h/ml (range of coefficient of variation values, 26 to 50). The dose-proportionality slope estimate (90% confidence interval) for AUC0-∞ was 1.30 (1.19 to 1.41), indicating a greater-than-dose-proportional increase. The data for safety in part 1 show that 29/72 subjects had ≥1 adverse event. Infusion site reactions were reported in 2/9 vehicle subjects, 0/18 placebo subjects, and 7/45 i.v. posaconazole subjects. The data for safety in part 2 show that infusion site reactions were reported in 1/4 (25%) placebo subjects, 3/9 (33%) vehicle control subjects, and 4/5 (80%) i.v. posaconazole (100 mg) subjects (3 posaconazole recipients subsequently developed thrombophlebitis and were discontinued from treatment). In conclusion, the posaconazole i.v. solution showed a greater-than-dose-proportional increase in exposure, primarily at doses below 200 mg. When administered peripherally at the same infusion site, multiple dosing of i.v. posaconazole led to unacceptably high rates of infusion site reactions. Intravenous posaconazole was otherwise well tolerated. Single doses of i.v. posaconazole were tolerated when given through a peripheral vein over 30 min.

Pharmacokinetic interaction between HCV protease inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy.

PURPOSE: Intravenous opioid use is a common route of hepatitis C virus (HCV) infection; consequently, the prevalence of HCV is high among patients on methadone or buprenorphine/naloxone. The authors evaluated the pharmacokinetic interaction of boceprevir with methadone or buprenorphine/naloxone in patients on stable maintenance therapy. METHODS: This was a two-center, open-label, fixed-sequence study in 21 adult volunteers on stable maintenance therapy. Oral methadone (20-150 mg once daily) or sublingual buprenorphine/naloxone (8/2-24/6 mg once daily) was administered alone or in combination with boceprevir (800 mg every 8 h) on days 2-7. Pharmacokinetic sampling occurred before and up to 24 h after the dose on days 1 and 7. RESULTS: Coadministration of boceprevir reduced the area under the concentration-time curve during a dosing interval τ (AUC τ ) and maximum observed plasma (or serum) concentration (C max) of R-methadone (geometric mean ratios (GMRs) [90 % confidence intervals (CIs)], 0.85 [0.74, 0.96] and 0.90 [0.71, 1.13]) and S-methadone (GMRs [90 % CIs], 0.78 [0.66, 0.93] and 0.83 [0.64, 1.09]). Boceprevir increased the AUC τ and C max of buprenorphine (GMRs [90 % CIs], 1.19 [0.91, 1.58] and 1.18 [0.93, 1.50]) and naloxone (GMRs [90 % CIs], 1.33 [0.90, 1.93] and 1.09 [0.79, 1.51]). Boceprevir exposure upon methadone or buprenorphine/naloxone coadministration was not clinically different from historical controls and there was no evidence of opioid withdrawal or excess. CONCLUSIONS: There was no clinically meaningful impact of boceprevir on methadone or buprenorphine pharmacokinetics, suggesting that methadone/buprenorphine dose adjustments are not required upon coadministration with boceprevir. Individual patients may differ in their clinical experience and clinicians should maintain vigilance when coadministering these medications.

Pharmacokinetic interactions between the hepatitis C virus protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, darunavir, and lopinavir.

BACKGROUND: Boceprevir represents a new treatment option for hepatitis C (HCV)-infected patients, including those with HCV/human immunodeficiency virus coinfection; however, little is known about pharmacokinetic interactions between boceprevir and antiretroviral drugs. METHODS: A randomized, open-label study to assess the pharmacokinetic interactions between boceprevir and ritonavir-boosted protease inhibitors (PI/r) was conducted in 39 healthy adults. Subjects received boceprevir (800 mg, 3 times daily) for 6 days and then received PI/r as follows: atazanavir (ATV) 300 mg once daily, lopinavir (LPV) 400 mg twice daily, or darunavir (DRV) 600 mg twice daily, each with ritonavir (RTV) 100 mg on days 10-31, plus concomitant boceprevir on days 25-31. RESULTS: Boceprevir decreased the exposure of all PI/r, with area under the concentration-time curve [AUC] from time 0 to the time of the last measurable sample geometric mean ratios of 0.65 (90% confidence interval [CI], .55-.78) for ATV/r; 0.66 (90% CI, .60-.72) for LPV/r, and 0.56 (90% CI, .51-.61) for DRV/r. Coadministration with boceprevir decreased RTV AUC during a dosing interval τ (AUC(τ)) by 22%-36%. ATV/r did not significantly affect boceprevir exposure, but boceprevir AUC(τ) was reduced by 45% and 32% when coadministered with LPV/r and DRV/r, respectively. Overall, treatments were well tolerated with no unexpected adverse events. CONCLUSIONS: Concomitant administration of boceprevir with PI/r resulted in reduced exposures of PI and boceprevir. These drug-drug interactions may reduce the effectiveness of PI/r and/or boceprevir when coadministered.

Pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers.

UNLABELLED: The hepatitis C virus protease inhibitor boceprevir is a strong inhibitor of cytochrome P450 3A4 and 3A5 (CYP3A4/5). Cyclosporine and tacrolimus are calcineurin inhibitor immunosuppressants used to prevent organ rejection after liver transplantation; both are substrates of CYP3A4. This two-part pharmacokinetic interaction study evaluated boceprevir with cyclosporine (part 1) and tacrolimus (part 2). In part 1, 10 subjects received single-dose cyclosporine (100 mg) on day 1, single-dose boceprevir (800 mg) on day 3, and concomitant cyclosporine/boceprevir on day 4. After washout, subjects received boceprevir (800 mg three times a day) for 7 days plus single-dose cyclosporine (100 mg) on day 6. In part 2A, 12 subjects received single-dose tacrolimus (0.5 mg). After washout, they received boceprevir (800 mg three times a day) for 11 days plus single-dose tacrolimus (0.5 mg) on day 6. In part 2B, 10 subjects received single-dose boceprevir (800 mg) and 24 hours later received boceprevir (800 mg) plus tacrolimus (0.5 mg). Coadministration of boceprevir with cyclosporine/tacrolimus was well tolerated. Concomitant boceprevir increased the area under the concentration-time curve from time 0 to infinity after single dosing (AUC(inf) ) and maximum observed plasma (or blood) concentration (C(max) ) of cyclosporine with geometric mean ratios (GMRs) (90% confidence interval [CI]) of 2.7 (2.4-3.1) and 2.0 (1.7-2.4), respectively. Concomitant boceprevir increased the AUC(inf) and C(max) of tacrolimus with GMRs (90% CI) of 17 (14-21) and 9.9 (8.0-12), respectively. Neither cyclosporine nor tacrolimus coadministration had a meaningful effect on boceprevir pharmacokinetics. CONCLUSION: Dose adjustments of cyclosporine should be anticipated when administered with boceprevir, guided by close monitoring of cyclosporine blood concentrations and frequent assessments of renal function and cyclosporine-related side effects. Administration of boceprevir plus tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus-related side effects.

Single-dose phase I study to evaluate the pharmacokinetics of posaconazole in new tablet and capsule formulations relative to oral suspension.

Posaconazole oral suspension, a marketed extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis, should be taken with food to maximize absorption. New tablet and capsule formulations have been developed in an attempt to optimize absorption and bioavailability. The aims of this exploratory open-label, partially randomized, 2-part, 4-way, single-dose crossover study in 16 healthy adults were to characterize pharmacokinetics for posaconazole tablet and capsule formulations relative to those for posaconazole oral suspension under fasted and fed conditions and to assess safety and tolerability. Under fasted conditions, posaconazole exposures (area under the curve [AUC]) for the tablet and capsule formulations were similar (mean AUC from time zero to infinity [AUC(0-∞)], tablet A, 11,700 ng · h/ml [coefficient of variation {CV}, 26%]; tablet B, 11,300 ng · h/ml [CV, 22%]; capsule, 11,000 ng · h/ml [CV, 25%]) and were substantially higher than the exposure for the oral suspension (mean AUC(0-∞), 3,420 ng · h/ml [CV, 44%]). Tablets and capsule showed less variability in exposure than the oral suspension. In fed subjects, tablets and capsule resulted in similar AUC values (mean AUC(0-∞), tablet A, 11,900 ng · h/ml [23%]; tablet B, 12,400 ng · h/ml [CV, 25%]; capsule, 12,300 ng · h/ml [CV, 28%]) and slightly higher exposure than the oral suspension (mean AUC(0-∞), 8,750 [CV, 24%]). Median times to the maximum concentration of drug in plasma were 4 to 5 h (fasted conditions) and 6 to 8 h (fed conditions). Mean half-lives values were similar for all formulations under fed and fasted conditions (23.1 to 29.2 h). Consistent with previous data, exposure for the oral suspension increased 2.5- to 3-fold when it was given with a high-fat meal. Conversely, exposures for tablets and capsule were not markedly affected by food. All formulations of posaconazole at 100 mg were safe and well tolerated.

Pharmacokinetics and Safety of PTC596, a Novel Tubulin-Binding Agent, in Subjects With Advanced Solid Tumors.

PTC596 is a novel, orally bioavailable, small-molecule tubulin-binding agent that reduces B-cell-specific Moloney murine leukemia virus insertion site 1 activity and is being developed for the treatment of solid tumors. A phase 1, open-label, multiple-ascending-dose study was conducted to evaluate the pharmacokinetics and safety of the drug in subjects with advanced solid tumors. PTC596 was administered orally biweekly based on body weight. Dose escalation followed a modified 3 + 3 scheme using doses of 0.65, 1.3, 2.6, 5.2, 7.0, and 10.4 mg/kg. Following oral administration, PTC596 was rapidly absorbed, and between 0.65 and 7.0 mg/kg reached a maximum plasma concentration 2 to 4 hours after dosing. Area under the plasma concentration-time curve increased proportionally with body weight-adjusted doses. Maximum plasma concentration increased with dose, although the increase was less than dose proportional at dose levels >2.6 mg/kg. No accumulation occurred after multiple administrations up to 7.0 mg/kg. PTC596 had a terminal half-life ranging 12 to 15 hours at all doses except for the highest dose of 10.4 mg/kg, where the half-life was approximately 20 hours. Overall, PTC596 was well tolerated. The most frequently reported PTC596-related treatment-emergent adverse events were mild to moderate gastrointestinal symptoms, including diarrhea (54.8%), nausea (45.2%), vomiting (35.5%), and fatigue (35.5%). Only 1 patient treated with 10.4 mg/kg experienced dose-limiting toxicity of neutropenia and thrombocytopenia, both of which were reversible. Stable disease as best overall response was observed among 7 patients, with 2 patients receiving the study drug up to 16 weeks. These results support the further development of PTC596 for the treatment of solid tumors.

Effect of vicriviroc on the QT/corrected QT interval and central nervous system in healthy subjects.

Vicriviroc is a CCR5 antagonist in clinical development for the treatment of HIV-1. Two phase I studies were conducted to assess the safety of vicriviroc. One study characterized the drug's potential to prolong the QT/corrected QT (QTc) interval and to induce arrhythmia. In this partially blind, parallel-group study, 200 healthy subjects aged 18 to 50 years were randomized in equal groups to the following regimens: (i) placebo for 9 days and a single dose of moxifloxacin at 400 mg on day 10, (ii) placebo, (iii) vicriviroc-ritonavir (30 and 100 mg), (iv) vicriviroc-ritonavir (150 and 100 mg), and (v) ritonavir (100 mg). The second study characterized the effects of a range of vicriviroc doses on the central nervous system (CNS). In this third-party-blind, parallel-group study, 30 healthy subjects aged 18 to 48 years were randomized to receive a single dose of either vicriviroc at 200, 250, or 300 mg or placebo, followed by multiple (seven) once-daily doses of either vicriviroc at 150, 200, or 250 mg or placebo, respectively. In the first study, vicriviroc produced no clinically meaningful effect on the QT/QTc interval when administered at a supratherapeutic or therapeutic dose concurrently with ritonavir. In the second study, vicriviroc produced no observable seizure activity, nor was it held to be associated with any clinically relevant changes in brain waveforms in the final consensus of reviewers. These findings showed that vicriviroc produced no clinically relevant QTc prolongation cardiac or epileptogenic effects in healthy individuals at exposures as high as five times those expected for HIV-infected patients receiving therapeutic doses of vicriviroc in a ritonavir-boosted protease inhibitor-containing regimen.

Antiviral Activity, Safety, and Tolerability of Multiple Ascending Doses of Elbasvir or Grazoprevir in Participants Infected With Hepatitis C Virus Genotype-1 or -3.

PURPOSE: Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3. METHODS: These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3. FINDINGS: Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log10 IU/mL for GT1- and GT3-infected participants. IMPLICATIONS: The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose-response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002).

Population pharmacokinetics of pomalidomide in patients with relapsed or refractory multiple myeloma with various degrees of impaired renal function.

Pomalidomide is an immunomodulatory drug for treatment of relapsed or refractory multiple myeloma (rrMM) in patients who often have comorbid renal conditions. To assess the impact of renal impairment on pomalidomide exposure, a population pharmacokinetics (PPK) model of pomalidomide in rrMM patients with various degrees of impaired renal function was developed. Intensive and sparse pomalidomide concentration data collected from two clinical studies in rrMM patients with normal renal function, moderately impaired renal function, severely impaired renal function not requiring dialysis, and with severely impaired renal function requiring dialysis were pooled over the dose range of 2 to 4 mg, to assess specifically the influence of the impaired renal function as a categorical variable and a continuous variable on pomalidomide clearance and plasma exposure. In addition, pomalidomide concentration data collected on dialysis days from both the withdrawal (arterial) side and from the returning (venous) side of the dialyzer, from rrMM patients with severely impaired renal function requiring dialysis, were used to assess the extent to which dialysis contributes to the removal of pomalidomide from blood circulation. PPK analyses demonstrated that moderate to severe renal impairment not requiring dialysis has no influence on pomalidomide clearance or plasma exposure, as compared to those patients with normal renal function, while pomalidomide exposure increased approximately 35% in patients with severe renal impairment requiring dialysis on nondialysis days. In addition, dialysis increased total body pomalidomide clearance from 5 L/h to 12 L/h, indicating that dialysis will significantly remove pomalidomide from the blood circulation. Thus, pomalidomide should be administered post-dialysis on the days of dialysis.

The effect of ravuconazole on the pharmacokinetics of nelfinavir in healthy male volunteers.

An open-label, nonrandomized study was conducted to assess the effect of ravuconazole on the pharmacokinetics of concomitantly administered nelfinavir. Healthy volunteers received 750 mg nelfinavir on day 1, 750 mg nelfinavir and 400 mg ravuconazole on day 2, 400 mg ravuconazole on days 3 to 28, and 750 mg nelfinavir and 400 mg ravuconazole on day 29. The geometric means of C(max) and area under the curve of nelfinavir coadministered with ravuconazole were 30.7% and 31.9% higher on day 2 and 7.9% and 16.2% lower on day 29, respectively, compared to the corresponding values on day 1. These findings are consistent with the potential for ravuconazole to both inhibit and induce CYP3A isozymes. The alterations in the systemic exposure to nelfinavir were within the range defined by the 90% confidence interval. The study data indicate that coadministration of ravuconazole did not result in a clinically significant change in the plasma levels of nelfinavir.

A Phase 1, double-blind, 4-period crossover study to investigate the effects of pomalidomide on QT interval in healthy male subjects.

PURPOSE: Pomalidomide is a distinct immunomodulatory agent approved for the treatment of relapsed and refractory multiple myeloma. QT interval was monitored in prior studies, and although there was no indication that pomalidomide could induce QT prolongation, a formal analysis was not previously conducted. Therefore, we present here the results of a study evaluating the effects of pomalidomide on QT interval corrected for heart rate (QTc) using Fridericia's formula (QTcF) and other electrocardiogram (ECG) parameters. METHODS: Healthy male volunteers with normal or clinically acceptable laboratory tests and ECG results were randomized to receive single oral doses of placebo, pomalidomide 4 mg, pomalidomide 20 mg, and moxifloxacin 400 mg (positive control) in different sequences. Subjects were evaluated by digital ECG monitoring and underwent blood sampling and standard safety monitoring. RESULTS: Seventy-two subjects were enrolled. In ECG evaluations performed after dosing with pomalidomide 4 mg (therapeutic dose) or 20 mg (supratherapeutic dose), the upper limit of the two-sided 90 % CI for mean change from baseline and placebo-corrected QTcF was <10 ms at all postdose time points, which is below the defined threshold of regulatory concern. In contrast, moxifloxacin induced a clear prolongation in QT interval. Changes in heart rate and other ECG parameters after pomalidomide dosing were clinically insignificant. CONCLUSIONS: Pomalidomide given as a single oral dose of up to 20 mg was not associated with QT prolongation in healthy male subjects.

Best practices for the use of itraconazole as a replacement for ketoconazole in drug-drug interaction studies.

Ketoconazole has been widely used as a strong cytochrome P450 (CYP) 3A (CYP3A) inhibitor in drug-drug interaction (DDI) studies. However, the US Food and Drug Administration has recommended limiting the use of ketoconazole to cases in which no alternative therapies exist, and the European Medicines Agency has recommended the suspension of its marketing authorizations because of the potential for serious safety concerns. In this review, the Innovation and Quality in Pharmaceutical Development's Clinical Pharmacology Leadership Group (CPLG) provides a compelling rationale for the use of itraconazole as a replacement for ketoconazole in clinical DDI studies and provides recommendations on the best practices for the use of itraconazole in such studies. Various factors considered in the recommendations include the choice of itraconazole dosage form, administration in the fasted or fed state, the dose and duration of itraconazole administration, the timing of substrate and itraconazole coadministration, and measurement of itraconazole and metabolite plasma concentrations, among others. The CPLG's recommendations are based on careful review of available literature and internal industry experiences.

Lack of an effect of atazanavir on steady-state pharmacokinetics of methadone in patients chronically treated for opiate addiction.

BACKGROUND: Effective antiretroviral treatment of opiate-addicted drug users with HIV infection often requires concomitant substance abuse treatment, commonly with methadone. Pharmacological interactions between antiretroviral drugs and methadone may result in opiate withdrawal or increased side effects. OBJECTIVES: To determine if atazanavir, a once-daily protease inhibitor and moderate inhibitor of P450 CYP3A4, exhibited pharmacokinetic interactions with (R)-methadone. METHODS: Methadone pharmacokinetic parameters were measured in 16 patients on chronic methadone therapy prior to and after 14 days of daily administration of atazanavir. Steady-state pharmacokinetic values for total, (R)- (active) and (S)- (inactive) isomers of methadone were derived from plasma concentrations versus time data. Symptoms of opiate withdrawal and excess were monitored. RESULTS: For the active isomer (R)-methadone, the ratio of geometric means for coadministration with atazanavir relative to methadone alone were 1.03 [90% confidence interval (CI), 0.95-1.10] for the area under the concentration-time curve (AUC), 0.91 (90% CI, 0.84-1.00) for plasma maximal concentration and 1.11 (90% CI, 1.02-1.20) for plasma trough concentration. Confidence intervals for all three were within the no-effect or bioequivalence range of 0.80-1.25 for (R)-methadone. Inactive (S)-methadone was modestly reduced during atazanavir coadministration. Clinically relevant symptoms of opiate withdrawal or excess were not detected. Exposures to atazanavir were within range of previously reported values. CONCLUSIONS: No clinically relevant pharmacokinetic interactions were found between atazanavir and methadone. Dosage adjustment need not be recommended for either methadone or atazanavir when co-administered to patients treated for opiate abuse and HIV disease.

The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults.

BACKGROUND: Therapy with some HIV protease inhibitors (PI) contributes to insulin resistance and type 2 diabetes mellitus, by inhibition of insulin-sensitive glucose transporters. Atazanavir (ATV) is a new PI with substantially less in vitro effect on glucose transport than observed with other PI, including lopinavir (LPV) or ritonavir (RTV). METHODS: Randomized, double-blind, crossover study of the effect of 5 days of administering ATV, lopinavir/ritonavir (LPV/r) or placebo on insulin-stimulated glucose disposal in 30 healthy HIV-negative subjects. Each subject was studied on two of three possible treatments with a wash-out period between treatments. RESULTS: The mean insulin-stimulated glucose disposal (mg/min per kg body weight) per unit insulin (microU/ml) (M/I) was 9.88, 9.80 and 7.52 for placebo, ATV and LPV/r, respectively (SEM, 0.84 for all). There was no significant difference between ATV and placebo. The M/I for LPV/r was 23% lower than that for ATV (P = 0.010) and 24% lower than that for placebo (P = 0.008). The mean glycogen storage rates were 3.85, 4.00 and 2.54 mg/min per kg for placebo, ATV and LPV/r, respectively (SEM, 0.39 for all). There was no significant difference between ATV and placebo. The glycogen storage rate for LPV/r was 36% lower than ATV (P = 0.003) and 34% lower than placebo (P = 0.006). CONCLUSIONS: ATV given to healthy subjects for 5 days did not affect insulin sensitivity, while LPV/r induced insulin resistance. This observation is consistent with differential in vitro effects of these PI on glucose transport. Further data are needed to assess clinical implications for body composition.

Effect of food on the oral bioavailability of didanosine from encapsulated enteric-coated beads.

The objective of this study was to assess the effect of food and timing of meals on the bioavailability of didanosine from encapsulated enteric-coated beads. Four different independent, open-label, single-dose, randomized, crossover studies were conducted in healthy subjects (n = 20-30). Didanosine (400 mg) was given concomitantly with a high-fat meal, light meal, yogurt, and applesauce. In addition, didanosine was given 1, 1.5, 2, and 3 hours before and 2 hours after a light meal. Statistical comparison with fasting conditions was made using the equivalence approach for Cmax (70%-143%) and AUC (80%-125%). The high-fat meal, light meal, yogurt, and applesauce decreased the Cmax by 46%, 22%, 30%, and 24%, respectively, and lowered the AUC by 19%, 27%, 20%, and 18%, respectively; statistical analyses indicated an indeterminate food effect, except for the Cmax for the high-fat meal. For 1 hour before meal, Cmax and AUC were lower by 15% and 24% and, for 2 hours after meal, were lower by 15% and 10%, respectively. There was an indeterminate food effect for 1 hour before the meal treatment; in addition, 2 hours after the meal, treatment approached statistical equivalence, missing narrowly on the lower bounds. For 1.5, 2, and 3 hours before meal treatments, Cmax values were unchanged, but AUC was lower by 10%, 4%, and 0%, respectively; lack of food effect was observed for all three treatments. Across studies, median time to Cmix ranged from 1.67 to 2.67 hours but was delayed by 2.5 to 3 hours with high-fat and light meals compared to fasting conditions. The half-life of didanosine was 1.5 to 2 hours. It was concluded that the bioavailability of didanosine from encapsulated enteric-coated beads was reduced by approximately 20% to 25% with food, which can be circumvented by taking didanosine on an empty stomach. The clinical significance of such moderate reductions in didanosine exposure with food, especially as part of a highly active antiretroviral therapy, is not clear.

Effect of posaconazole on the pharmacokinetics of simvastatin and midazolam in healthy volunteers.

OBJECTIVES: The aim of the study is to determine the effect of posaconazole , an extended-spectrum triazole, on the pharmacokinetics of the HMG-CoA reductase inhibitor, simvastatin. METHODS: This randomized, fixed-sequence, parallel-group, single-center, open-label study was conducted in 35 healthy volunteers randomly assigned to receive one of three doses of oral posaconazole: 50, 100 or 200 mg. All subjects received single doses of the reference drug midazolam (2 mg oral) alone on day -9; simvastatin (40 mg oral) alone on day -6; posaconazole (50, 100 or 200 mg) on days 1 - 7 once daily (q.d.); posaconazole plus midazolam (day 8); posaconazole alone (days 9 - 10); posaconazole plus simvastatin (day 11) and posaconazole alone (days 12 - 13). RESULTS: Relative to simvastatin alone, posaconazole (50, 100 and 200 mg q.d.) significantly increased the C(max) and AUC of simvastatin (5- to 11-fold increase in AUC) and simvastatin acid (5- to 8-fold increase in AUC) during co-administration. Relative to midazolam alone, posaconazole (50, 100 and 200 mg q.d.) significantly inhibited CYP3A4-mediated metabolism of midazolam (three to sixfold increase in AUC). CONCLUSION: These findings support the classification of posaconazole as a strong CYP3A4 inhibitor. Simvastatin, or other statins predominantly metabolized by CYP3A4, should not be co-administered with posaconazole. Other statins, whose metabolism/elimination is not affected by CYP3A4 inhibition, should be considered for co-administration.

Single-dose pharmacokinetics of boceprevir in subjects with impaired hepatic or renal function.

BACKGROUND AND OBJECTIVE: Boceprevir is a novel inhibitor of the hepatitis C virus NS3 protease and was recently approved for the treatment of patients with chronic hepatitis C infection. The objective of this study was to evaluate the impact of impaired hepatic or renal function on boceprevir pharmacokinetics and safety/tolerability. METHODS: We conducted two open-label, single-dose, parallel-group studies comparing the safety and pharmacokinetics of boceprevir in patients with varying degrees of hepatic impairment compared with healthy controls in one study and patients with end-stage renal disease (ESRD) on haemodialysis with healthy controls in the other. Patients with hepatic impairment (mild [n = 6], moderate [n = 6], severe [n = 6] and healthy controls [n = 6]) received a single dose of boceprevir (400 mg) on day 1, and whole blood was collected at selected timepoints up to 72 hours postdose to measure plasma drug concentrations. Patients with ESRD and healthy subjects received a single dose of boceprevir 800 mg orally on days 1 and 4, with samples for pharmacokinetic analyses collected at selected timepoints up to 48 hours postdose on both days. In addition, 4 hours after dosing on day 4, patients with ESRD underwent haemodialysis with arterial and venous blood samples collected up to 8 hours postdose. RESULTS: In the hepatic impairment study, there was a trend toward increased mean maximum (peak) plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) of boceprevir with increasing severity of liver impairment. Point estimates for the geometric mean ratio for C(max) ranged from 100% in patients with mild hepatic impairment to 161% in patients with severe hepatic impairment, with the geometric mean ratio for AUC ranging from 91% in patients with mild hepatic impairment to 149% for patients with severe hepatic impairment, relative to healthy subjects. The mean elimination half-life (t(1/2;)) and median time to C(max) (t(max)) values of boceprevir were similar in healthy subjects and patients with hepatic impairment. In the renal impairment study, mean boceprevir C(max) and AUC values were comparable in patients with ESRD and in healthy subjects, with point estimates for the geometric mean ratio of 81% and 90%, respectively, compared with healthy subjects. Mean t(1/2;), median t(max) and mean apparent oral total clearance (CL/F) values were similar in healthy subjects and patients with ESRD. Boceprevir exposure was also similar in patients with ESRD on day 1 (no dialysis) and day 4 (dialysis beginning 4 hours postdose), with point estimates for the geometric mean ratio of C(max) and AUC to the last measurable sampling time (AUC(last)) on day 1 compared with day 4 of 88% and 98%, respectively. Treatment-emergent adverse events were reported in one patient with severe hepatic impairment (mild vomiting) and two patients with ESRD (moderate ventricular extrasystoles, flatulence and catheter thrombosis). CONCLUSION: In the present studies, the pharmacokinetic properties of boceprevir were not altered to a clinically meaningful extent in patients with impaired liver or renal function. These data indicate that boceprevir dose adjustment is not warranted in patients with impaired hepatic function or ESRD, including those receiving dialysis. Boceprevir is not removed by haemodialysis.

Pharmacokinetic interaction of vicriviroc with other antiretroviral agents: results from a series of fixed-sequence and parallel-group clinical trials.

BACKGROUND: Vicriviroc is a next-generation antiretroviral compound that blocks HIV from entering uninfected cells by binding to the virus's cellular co-receptor chemokine receptor 5 (CCR5). A potent inhibitor of HIV infection of human cells both in vitro and in vivo, vicriviroc is in development for use in treatment-naïve HIV-1-infected individuals. These patients often receive antiretroviral therapy regimens that include a ritonavir-enhanced protease inhibitor. Such regimens have a high potential for drug-drug interactions because many of the antiretroviral agents inhibit or induce elements of drug elimination pathways, such as the hepatic cytochromes, which may alter drug concentrations and affect both safety and efficacy. The aim of this set of studies was to determine what, if any, dose adjustments or monitoring would be required to use vicriviroc in regimens containing the most common antiretroviral agents. METHODS: Drug-drug interactions between vicriviroc and 11 other antiretroviral compounds were investigated in fixed-sequence or parallel-group clinical trials lasting 12-35 days. Fixed-sequence studies were conducted with the protease inhibitors atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, saquinavir and tipranavir. In these studies vicriviroc was administered with ritonavir for a fixed duration, followed by administration of vicriviroc with ritonavir plus the protease inhibitor. Parallel-group studies conducted with lopinavir, zidovudine/lamivudine and tenofovir disoproxil fumarate randomized subjects to receive vicriviroc with or without the study drug. All subjects enrolled in the studies were healthy male and female adults. STATISTICAL METHODS: The log-transformed data for vicriviroc primary pharmacokinetic parameters on appropriate days were statistically analysed using a one-way analysis of variance (ANOVA) model extracting the effects due to treatment. Steady state was evaluated by an ANOVA model on trough concentrations using day and subject as class variables. RESULTS: Vicriviroc exposure was not affected by the concurrently administered antiretroviral drugs in any clinically relevant manner, nor did vicriviroc have a clinically relevant effect on the exposure of other drugs. The drug combinations studied were safe and well tolerated, with most adverse events reported as mild to moderate. Aside from the known toxicities of the other antiretroviral drugs, no clinically relevant changes in blood chemistry, haematological parameters, ECGs or vital signs were associated with either vicriviroc or combination treatment. CONCLUSIONS: No dose modification or monitoring of vicriviroc concentrations is necessary when vicriviroc is co-administered with any of the antiretroviral agents reviewed here. The lack of drug-drug interactions suggests that it will be possible to add vicriviroc at the single clinically prescribed dose level to various background regimens that include a boosted protease inhibitor, with all other drugs also prescribed at their standard doses.

Effect of vicriviroc with or without ritonavir on oral contraceptive pharmacokinetics: a randomized, open-label, parallel-group, fixed-sequence crossover trial in healthy women.

BACKGROUND: Because women of childbearing potential represent 20% to 25% of the HIV population, it is important to determine any potential drug interactions between vicriviroc, an antiretroviral agent, and an oral contraceptive (OC) to provide guidance on any potential dose adjustments. OBJECTIVE: The primary study objective was to determine the effect of vicriviroc, a C-C chemokine receptor type 5 inhibitor, alone or in the presence of ritonavir, on the pharmacokinetics (AUC and C(max)) of the study OC (ethinyl estradiol [EE] 0.035 mg + norethindrone [NET] 1 mg). A secondary objective was to monitor the safety and tolerability of vicriviroc plus an OC with and without ritonavir. METHODS: This was a randomized, open-label, parallel-group, single-center study with a fixed-sequence crossover design. Female subjects were randomized into 2 groups and treated for 2 menstrual cycles. In cycle 1, all received the OC alone, per standard 28-day pack instructions. On the first 10 days of cycle 2, group 1 received OC + vicriviroc and group 2 received OC + ritonavir; on the following 11 days, both groups received OC + vicriviroc + ritonavir. Blood samples were collected up to 24 hours after dosing on prespecified days. Pharmacokinetic parameters, including AUC(0-24), C(max), and C(min), were calculated using noncompartmental methods, and drug interactions were evaluated using an ANOVA model by treatment group. Adverse events were collected using physical examination, vital sign measurements, clinical laboratory analysis, electrocardiography, and questioning at predefined time points throughout the study to assess the safety profile. RESULTS: Twenty-seven subjects were enrolled (26 white, 1 black). The median age and body mass index were 21 years (range, 18-36 years) and 24.5 kg/m(2) (range, 19.1-31.3 kg/m(2)), respectively. Twenty-one subjects completed the study and were included in the pharmacokinetic analysis; 4 discontinued for reasons unrelated to study drug and 2 discontinued because of adverse events. Vicriviroc had little effect on the pharmacokinetics of the OC. EE mean ratio estimates for C(max) and AUC(0-24) compared with OC administered alone were 91% and 97%, respectively, and for NET were 106% and 93%. Subjects receiving ritonavir, alone or with vicriviroc, experienced decreases in exposure of EE (C(max) mean ratio estimates, 89% and 76%; AUC(0-24) mean ratio estimates, 71% each, for ritonavir alone and ritonavir with vicriviroc, respectively) and, to a lesser extent, decreases in NET (C(max) mean ratio estimates 89% each; AUC(0-24) mean ratio estimates: 93% and 83%, for ritonavir alone and ritonavir with vicriviroc, respectively). Twenty-two of 27 (81%) subjects reported ≥1 treatment-emergent adverse event (TEAE). During cycle 1, TEAEs were reported for 18 of 27 (67%) subjects while receiving OC alone and for 3 of 24 (13%) subjects while receiving placebo OC. During cycle 2, TEAEs were reported for 8 of 12 (67%) subjects while receiving vicriviroc with OC, 4 of 12 (33%) subjects while receiving ritonavir with OC, 7 of 22 (32%) subjects while receiving vicriviroc + ritonavir with OC, and 2 of 22 (9%) subjects while receiving placebo OC. The most commonly reported TEAE was headache (vicriviroc + OC, n = 1; ritonavir + OC, n = 3; vicriviroc + ritonavir + OC, n = 2; OC alone, n = 12; placebo OC, n = 2). No TEAEs were considered severe. CONCLUSIONS: In this population of healthy female subjects, vicriviroc had little effect on the pharmacokinetics of EE or NET, whereas ritonavir, alone or with vicriviroc, was associated with consistent decrease in exposure of EE and a lesser decrease in NET.