Jan M. Wruck

Pharmacokinetic Interactions Between Buprenorphine/Naloxone and Tipranavir/Ritonavir in HIV-Negative Subjects Chronically Receiving Buprenorphine/Naloxone

HIV-infected patients with opioid dependence often require opioid replacement therapy. Pharmacokinetic interactions between HIV therapy and opioid dependence treatment medications can occur. HIV-seronegative subjects stabilized on at least 3 weeks of buprenorphine/naloxone (BUP/NLX) therapy sequentially underwent baseline and steady-state pharmacokinetic evaluation of open-label, twice daily tipranavir 500 mg co-administered with ritonavir 200 mg (TPV/r). Twelve subjects were enrolled and 10 completed the study. Prior to starting TPV/r, the geometric mean BUP AUC(0-24h) and C(max) were 43.9 ng h/mL and 5.61 ng/mL, respectively. After achieving steady-state with TPV/r (> or = 7 days), these values were similar at 43.7 ng h/mL and 4.84 ng/mL, respectively. Similar analyses for norBUP, the primary metabolite of BUP, demonstrated a reduction in geometric mean for AUC(0-24h) [68.7-14.7 ng h/mL; ratio=0.21 (90% CI 0.19-0.25)] and C(max) [4.75-0.94 ng/mL; ratio=0.20 (90% CI 0.17-0.23)]. The last measurable NLX concentration (C(last)) in the concentration-time profile, never measured in previous BUP/NLX interaction studies with antiretroviral medications, was decreased by 20%. Despite these pharmacokinetic effects on BUP metabolites and NLX, no clinical opioid withdrawal symptoms were noted. TPV steady-state AUC(0-12h) and C(max) decreased 19% and 25%, respectively, and C(min) was relatively unchanged when compared to historical control subjects receiving TPV/r alone. No dosage modification of BUP/NLX is required when co-administered with TPV/r. Though mechanistically unclear, it is likely that decreased plasma RTV levels while on BUP/NLX contributed substantially to the decrease in TPV levels. BUP/NLX and TPV/r should therefore be used cautiously to avoid decreased efficacy of TPV in patients taking these agents concomitantly.

Steady-State Disposition of the Nonpeptidic Protease Inhibitor Tipranavir when Coadministered with Ritonavir

ABSTRACT The pharmacokinetic and metabolite profiles of the antiretroviral agent tipranavir (TPV), administered with ritonavir (RTV), in nine healthy male volunteers were characterized. Subjects received 500-mg TPV capsules with 200-mg RTV capsules twice daily for 6 days. They then received a single oral dose of 551 mg of TPV containing 90 μCi of [14C]TPV with 200 mg of RTV on day 7, followed by twice-daily doses of unlabeled 500-mg TPV with 200 mg of RTV for up to 20 days. Blood, urine, and feces were collected for mass balance and metabolite profiling. Metabolite profiling and identification was performed using a flow scintillation analyzer in conjunction with liquid chromatography-tandem mass spectrometry. The median recovery of radioactivity was 87.1%, with 82.3% of the total recovered radioactivity excreted in the feces and less than 5% recovered from urine. Most radioactivity was excreted within 24 to 96 h after the dose of [14C]TPV. Radioactivity in blood was associated primarily with plasma rather than red blood cells. Unchanged TPV accounted for 98.4 to 99.7% of plasma radioactivity. Similarly, the most common form of radioactivity excreted in feces was unchanged TPV, accounting for a mean of 79.9% of fecal radioactivity. The most abundant metabolite in feces was a hydroxyl metabolite, H-1, which accounted for 4.9% of fecal radioactivity. TPV glucuronide metabolite H-3 was the most abundant of the drug-related components in urine, corresponding to 11% of urine radioactivity. In conclusion, after the coadministration of TPV and RTV, unchanged TPV represented the primary form of circulating and excreted TPV and the primary extraction route was via the feces.

Pharmacokinetic Assessment of Nevirapine and Metabolites in Human Immunodeficiency Virus Type 1-Infected Patients with Hepatic Fibrosis

ABSTRACT Nevirapine is a nonnucleoside reverse transcriptase inhibitor used as part of combination therapy for human immunodeficiency virus (HIV) infection. Nevirapine may be prescribed for patients with hepatic fibrosis and cirrhosis. Significant autoinduction of cytochrome P450 3A4 and 2B6 following multiple dosing prompted an assessment of the metabolic profiles in patients with liver disease receiving chronic nevirapine therapy. HIV-infected patients with hepatic fibrosis who were receiving a stable antiretroviral regimen containing nevirapine for ≥6 weeks had liver biopsy specimens assessed by Ishak histologic scoring and were grouped by severity (group 1, Ishak scores of 1 and 2; group 2, Ishak scores of 3 and 4; group 3, Ishak scores of 5 and 6). Steady-state trough nevirapine levels were determined for all patients, and additional measurements were obtained at 1, 2, and 4 h following nevirapine dosing for a subset of patients. The pharmacokinetics of nevirapine and its five metabolites were characterized, and a comparison of the results for the different Ishak groups was performed. Among 51 patients with hepatic fibrosis, the majority of whom were coinfected with hepatitis C virus or hepatitis B virus, differences between the maximum and the minimum observed plasma concentrations demonstrated a statistically significant flattening of the systemic exposure curves with progression from Ishak group 1 to Ishak group 2 or 3, suggesting a decrease in systemic clearance with the progression of liver disease. However, there were no significant differences in the trough and the maximum nevirapine concentrations between the Ishak groups. The metabolite profiles were also comparable across the Ishak groups. In HIV-infected patients who were chronically treated with nevirapine and who had various degrees of hepatic fibrosis, including cirrhosis, trough plasma nevirapine concentrations were not significantly increased, and thus, no dose adjustment is warranted.

MP09-10 TAMSULOSIN PRESCRIBING PATTERNS BASED ON A UNITED STATES HEALTH PLAN CLAIMS DATABASE

METHODS: We conducted a Cochrane review based on an a priori, protocol that included published and unpublished randomized controlled trials (RCTs) in any language. We excluded trials of children or adults with primary or secondary enuresis or underlying medical disorders. Primary outcomes were the number of nocturnal voids, quality of life (QoL), and major adverse events (AEs); secondary outcomes were duration of first sleep episode, time to first void, minor AEs, and treatment withdrawal due to AEs. We performed meta-analysis using RevMan 5.3 and rated the quality of evidence using GRADE. RESULTS: Of 271 studies identified through our search, we included 10 studies. Desmopressin was associated with a small decrease in the number of nocturnal voids (mean difference [MD] -1.1, 95% confidence interval [CI] -1.4 to -0.9; low quality evidence) and similar rates of major AEs (risk ratio [RR] 0.9, 95% CI 0.1 to 9.0; very low quality of evidence). We found no evidence for QoL. Compared to alpha-blockers, there was a similar reduction in the number of nocturnal voids (MD -0.2, 95% CI 01.2 to 0.7; very low quality evidence) and similar quality of life (MD -0.2, 95% CI -0.4 to 0.1; moderate quality of evidence). Rates of major AEs were similar (RR not estimable; low quality evidence). CONCLUSIONS: Current best evidence from RCTs in men with the chief complaint of nocturia suggests that desmopressin may result in a small reduction in the number of nocturnal voids with similar major AE rates compared to placebo. We are uncertain whether it reduces the number of nocturnal voids similarly to alpha-blockers. Additional welldesigned studies using active controls are needed.