John P. Sabo

Pharmacokinetic Characterization of Different Dose Combinations of Coadministered Tipranavir and Ritonavir in Healthy Volunteers

Abstract Purpose: To characterize the steady-state pharmacokinetic combination of the nonpeptidic protease inhibitor tipranavir (TPV) with ritonavir (RTV) in 95 healthy adult volunteers, a phase 1, single-center, open-label, randomized, parallel-group trial was conducted. Method: Participants received 250-mg self-emulsifying drug delivery system (SEDDS) capsules of TPV at doses between 250 mg and 1250 mg twice daily for 11 days, then received one or two RTV 100-mg SEDDS capsules, in addition to the TPV capsules, for the next 21 days. Results: Coadministration of TPV and RTV (TPV/r) resulted in a greater than 20-fold increase in steady-state TPV trough concentrations (Cssmin) as compared with TPV at steady state alone. Mean TPV Cssmin was above a preliminary target threshold of 20 μM with all but one of the RTV-boosted doses; without boosting, none of the TPV-alone doses exceeded the threshold. The average steady-state Cssmin for TPV 500 mg and 750 mg with RTV 100 mg or 200 mg were 20 to 57 times the protein-adjusted TPV IC90 for protease inhibitor-resistant HIV-1. An erythromycin breath test, a surrogate marker for cytochrome P450 isoenzyme 3A4 activity, indicated that all TPV/r combinations given provided net inhibition of this isoenzyme. The most frequent treatment-related adverse events were mild gastrointestinal symptoms. Conclusion: This phase 1 study demonstrated that RTV-boosted TPV achieves concentrations that are expected to be effective in treating drug-experienced patients.

Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers

The results of two randomized, single‐dose, crossover bioavailability studies are presented which describe the pharmacokinetics and oral bioavailability of nevirapine, a novel nonnucleoside antiretroviral drug. In the first study 12 healthy male volunteers received nevirapine 15 mg via short‐term i.v. infusion or orally as a 50 mg tablet or reference solution (50 mg/200 mL). Following the i.v. dose, nevirapine had a low systemic clearance (Mean±S.D., Cl=1.4±0.3 L/h) and a prolonged elimination phase (t1/2β=52.8±14.8 h; MRT=81.4±22.4 h). Nevirapine absolute bioavailability was 93±9% and 91±8% for the tablet and oral solution, respectively. In the second study, 24 healthy male volunteers were administered nevirapine as a 200 mg production‐line tablet or oral reference solution (200 mg/200 mL). There was no significant difference in bioavailability between the tablet and reference solution. Overall, comparison of the pharmacokinetic parameters between the 50 and 200 mg doses indicates that nevirapine is well absorbed at clinically relevant doses. The absorption profiles using deconvolution revealed no evidence of differential enzyme induction between the two doses or routes of administration following a single dose. Copyright

Pharmacokinetics of nevirapine and lamivudine in patients with HIV-1 infection.

The purpose of this parallel treatment group, double-blind. multicenter study was to lharacterize the pharmacokinetics of nevirapine and lamivudine when coadministered to patients with the HIV-1 infection. This pharmacokinetic interaction study was nested within a larger Phase III clinical trial conducted to characterize the safety and efficacy of coadministered nevirapine and lamivudine. One hundred HIV-1 infected patients with CD4+ lymphocyte counts=200 cells/mm3 and who were on a background of nucleoside (zidovudine [ZDV], didanosine [ddl], zalcitabine [ddC], stavudine [d4T]) therapy were randomly assigned to be treated with either nucleoside+ lamivudine+nevirapine or nucleoside+lamivudine+ placebo. Each patient underwent blood sampling at defined times for the purpose of determining the concentration of nevirapine in plasma and lamivudine in serum under steady-state conditions. Each patient was also monitored closely for concomitant administration of other drugs, including ZDV, ddl, ddC, d4T and cotrimoxazole. The pharmacokinetics of nevirapine and lamivudine were characterized using nonlinear mixed-effects modeling. There were no reported serious adverse events during the 40-day pharmacokinetic study. The results of the modeling analysis revealed that nevirapine had no effect on the pharmacokinetics of lamivudine. Estimates of the apparent clearance for nevirapine (CL/F=3.3 L/hour; 95% confidence interval [Cl] 2.9 to 3.7 L/hour) and lamivudine (CL/F 27.6 L/hour; 95% Cl 22 to 33.2 L/hour) were consistent with the values reported in earlier trials. However, the results also showed that concomitant administration of lamivudine with cotrimoxazole resulted in a 31% reduction in the apparent clearance of lamivudine, resulting in a 43% increase in the average steady-state lamivudine serum concentrations. These results indicate that chronic concurrent administration of cotrimoxazole with lamivudine may significantly affect the steady-state pharmacokinetics of lamivudine.

Interaction of Ritonavir-Boosted Tipranavir with Loperamide Does Not Result in Loperamide-Associated Neurologic Side Effects in Healthy Volunteers

ABSTRACT Loperamide (LOP) is a peripherally acting opioid receptor agonist used for the management of chronic diarrhea through the reduction of gut motility. The lack of central opioid effects is partly due to the efflux activity of the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier. The protease inhibitors are substrates for P-gp and have the potential to cause increased LOP levels in the brain. Because protease inhibitors, including tipranavir (TPV), are often associated with diarrhea, they are commonly used in combination with LOP. The level of respiratory depression, the level of pupil constriction, the pharmacokinetics, and the safety of LOP alone compared with those of LOP-ritonavir (RTV), LOP-TPV, and LOP-TPV-RTV were evaluated in a randomized, open-label, parallel-group study with 24 healthy human immunodeficiency virus type 1-negative adults. Respiratory depression was assessed by determination of the ventilatory response to carbon dioxide. Tipranavir-containing regimens (LOP-TPV and LOP-TPV-RTV) caused decreases in the area under the concentration-time curve from time zero to infinity for LOP (51% and 63% decreases, respectively) and its metabolite (72% and 77% decreases, respectively), whereas RTV caused increases in the levels of exposure of LOP (121% increase) and its metabolite (44% increase). In vitro and in vivo data suggest that TPV is a substrate for and an inducer of P-gp activity. The respiratory response to LOP in combination with TPV and/or RTV was not different from that to LOP alone. There was no evidence that LOP had opioid effects in the central nervous system, as measured indirectly by CO2 response curves and pupillary response in the presence of TPV and/or RTV.

Differential Effects of Tipranavir plus Ritonavir on Atorvastatin or Rosuvastatin Pharmacokinetics in Healthy Volunteers

ABSTRACT To identify pharmacokinetic (PK) drug-drug interactions between tipranavir-ritonavir (TPV/r) and rosuvastatin and atorvastatin, we conducted two prospective, open-label, single-arm, two-period studies. The geometric mean (GM) ratio was 1.37 (90% confidence interval [CI], 1.15 to 1.62) for the area under the concentration-time curve (AUC) for rosuvastatin and 2.23 (90% CI, 1.83 to 2.72) for the maximum concentration of drug in serum (Cmax) for rosuvastatin with TPV/r at steady state versus alone. The GM ratio was 9.36 (90% CI, 8.02 to 10.94) for the AUC of atorvastatin and 8.61 (90% CI, 7.25 to 10.21) for the Cmax of atorvastatin with TPV/r at steady state versus alone. Tipranavir PK parameters were not affected by single-dose rosuvastatin or atorvastatin. Mild gastrointestinal intolerance, headache, and mild reversible liver enzyme elevations (grade 1 and 2) were the most commonly reported adverse drug reactions. Based on these interactions, we recommend low initial doses of rosuvastatin (5 mg) and atorvastatin (10 mg), with careful clinical monitoring of rosuvastatin- or atorvastatin-related adverse events when combined with TPV/r.

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.

Combined tipranavir and enfuvirtide use associated with higher plasma tipranavir concentrations but not with increased hepatotoxicity: sub-analysis from RESIST.

In RESIST, enfuvirtide co-administered with ritonavir-boosted tipranavir was associated with higher plasma tipranavir concentrations, which seldom rose above those associated with an increased risk of grade 3/4 transaminase elevations. Transaminase elevation rates (6.5%) and clinical hepatic event rates (5.9 events/100 person exposure years) were lower in the tipranavir/ritonavir with enfuvirtide group than in the tipranavir/ritonavir without enfuvirtide group. Observed increases in plasma tipranavir concentrations thus had no apparent effect on the risk of hepatotoxicity.

Interaction Studies of Tipranavir-Ritonavir with Clarithromycin, Fluconazole, and Rifabutin in Healthy Volunteers

ABSTRACT Three separate controlled, two-period studies with healthy volunteers assessed the pharmacokinetic interactions between tipranavir-ritonavir (TPV/r) in a 500/200-mg dose and 500 mg of clarithromycin (CLR), 100 mg of fluconazole (FCZ), or 150 mg of rifabutin (RFB). The CLR study was conducted with 24 subjects. The geometric mean ratios (GMR) and 90% confidence intervals (90% CI; given in parentheses) of the areas under the concentration-time curve (AUC), the maximum concentrations of the drugs in serum (Cmax), and the concentrations in serum at 12 h postdose (Cp12h) for multiple-dose TPV/r and multiple-dose CLR, indicating the effect of TPV/r on the CLR parameters, were 1.19 (1.04-1.37), 0.95 (0.83-1.09), and 1.68 (1.42-1.98), respectively. The formation of the metabolite 14-OH-CLR was decreased by 95% in the presence of TPV, and the TPV AUC increased 66% compared to that for human immunodeficiency virus (HIV)-negative historical controls. The FCZ study was conducted with 20 subjects. The GMR (and 90% CI) of the AUC, Cmax, and Cp24h, indicating the effect of multiple-dose TPV/r on the multiple-dose FCZ parameters, were 0.92 (0.88-0.95), 0.94 (0.91-0.98), and 0.89 (0.85-0.92), respectively. The TPV AUC increased by 50% compared to that for HIV-negative historical controls. The RFB study was conducted with 24 subjects. The GMR (and 90% CI) of the AUC, Cmax, and Cp12h for multiple-dose TPV/r and single-dose RFB, indicating the effect of TPV/r on the RFB parameters, were 2.90 (2.59-3.26), 1.70 (1.49-1.94), and 2.14 (1.90-2.41), respectively. The GMR (and 90% CI) of the AUC, Cmax, and Cp12h of TPV/r and RFB with 25-O-desacetyl-RFB were 4.33 (3.86-4.86), 1.86 (1.63-2.12), and 2.76 (2.44-3.12), respectively. Coadministration of TPV with a single dose of RFB resulted in a 16% increase in the TPV Cp12h compared to that for TPV alone. In the general population, no dose adjustments are necessary for the combination of TPV/r and CLR or FCZ. Combining TPV/r with RFB should be done with caution, while toxicity and RFB drug levels should be monitored. Study medications were generally well-tolerated in these studies.

Contribution of Major Metabolites toward Complex Drug-Drug Interactions of Deleobuvir: In Vitro Predictions and In Vivo Outcomes

The drug-drug interaction (DDI) potential of deleobuvir, an hepatitis C virus (HCV) polymerase inhibitor, and its two major metabolites, CD 6168 (formed via reduction by gut bacteria) and deleobuvir-acyl glucuronide (AG), was assessed in vitro. Area-under-the-curve (AUC) ratios (AUCi/AUC) were predicted using a static model and compared with actual AUC ratios for probe substrates in a P450 cocktail of caffeine (CYP1A2), tolbutamide (CYP2C9), and midazolam (CYP3A4), administered before and after 8 days of deleobuvir administration to HCV-infected patients. In vitro studies assessed inhibition, inactivation and induction of P450s. Induction was assessed in a short-incubation (10 hours) hepatocyte assay, validated using positive controls, to circumvent cytotoxicity seen with deleobuvir and its metabolites. Overall, P450 isoforms were differentially affected by deleobuvir and its two metabolites. Of note was more potent CYP2C8 inactivation by deleobuvir-AG than deleobuvir and P450 induction by CD 6168 but not by deleobuvir. The predicted net AUC ratios for probe substrates were 2.92 (CYP1A2), 0.45 (CYP2C9), and 0.97 (CYP3A4) compared with clinically observed ratios of 1.64 (CYP1A2), 0.86 (CYP2C9), and 1.23 (CYP3A4). Predictions of DDI using deleobuvir alone would have significantly over-predicted the DDI potential for CYP3A4 inhibition (AUC ratio of 6.15). Including metabolite data brought the predicted net effect close to the observed DDI. However, the static model over-predicted the induction of CYP2C9 and inhibition/inactivation of CYP1A2. This multiple-perpetrator DDI scenario highlights the application of the static model for predicting complex DDI for CYP3A4 and exemplifies the importance of including key metabolites in an overall DDI assessment.