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

MacGregor, Thomas R.; Sabo, John P.; Norris, Stephen H.; Johnson, Philip A.; Galitz, Lawrence; McCallister, Scott

doi:10.1310/rrx7-49me-27v7-mwwv

Cited by 58 publications

(37 citation statements)

References 15 publications

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“…Ritonavir is a protease inhibitor clinically used as an anti-HIV drug. It also widely used as a CYP3A4 inhibitor to boost the effect of other anti-HIV agents for the treatment of AIDS [23] . Some research has indicated that the elevation and prolongation of the plasma levels of some protease inhibitors (such as tipranavir, saquinavir or indinavir) by ritonavir coadministration may produce a composite suppression of HIV viral replication in excess of the sum of that was observed with either agent individually [24,25] .…”

Section: Discussionmentioning

confidence: 99%

Metabolism of novel anti-HIV agent 3-cyanomethyl-4-methyl-DCK by human liver microsomes and recombinant CYP enzymes

Zhuang¹,

Deng²,

Li³

et al. 2011

Acta Pharmacol Sin

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Aim:To investigate the metabolism of 3-cyanomethyl-4-methyl-DCK (CMDCK), a novel anti-HIV agent, by human liver microsomes (HLMs) and recombinant cytochrome P450 enzymes (CYPs). Methods: CMDCK was incubated with HLMs or a panel of recombinant cytochrome P450 enzymes including CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5. LC-ion trap mass spectrometry was used to separate and identify CMDCK metabolites. In the experiments with recombinant cytochrome P450 enzymes, specific chemical inhibitors combined with CYP antibodies were used to identify the CYP isoforms involved in CMDCK metabolism. Results: CMDCK was rapidly and extensively metabolized by HLMs. Its intrinsic hepatic clearance estimated from the in vitro data was 19.4 mL·min -1 ·kg -1 , which was comparable to the mean human hepatic blood flow rate (20.7 mL·min -1 ·kg -1 ). The major metabolic pathway of CMDCK was oxidation, and a total of 14 metabolites were detected. CYP3A4 and 3A5 were found to be the principal CYP enzymes responsible for CMDCK metabolism. Conclusion: CMDCK was metabolized rapidly and extensively in human hepatic microsomes to form a number of oxidative metabolites. CYP3A4 and 3A5 were the predominant enzymes responsible for the oxidation of CMDCK.

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Section: Discussionmentioning

confidence: 99%

Metabolism of novel anti-HIV agent 3-cyanomethyl-4-methyl-DCK by human liver microsomes and recombinant CYP enzymes

Zhuang¹,

Deng²,

Li³

et al. 2011

Acta Pharmacol Sin

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“…In vitro data have shown that resistance to TPV develops slowly (5). When TPV is coadministered with ritonavir (RTV) as a booster, TPV has been shown to have potent antiviral activity in multidrug-experienced patients (3,6,9,12). In the RESIST-1 and the RESIST-2 studies, the efficacy and safety of TPV-RTV (500 mg/200 mg twice daily) in 1,509 highly treatment-experienced HIV-1-positive patients were assessed.…”

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Tipranavir (TPV) Genotypic Inhibitory Quotient Predicts Virological Response at 48 Weeks to TPV-Based Salvage Regimens

Requena

Bonora

Calcagno

et al. 2008

Antimicrob Agents Chemother

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The virological response (VR) to a tipranavir-ritonavir (TPV-RTV)-based regimen had been shown to be associated with a number of mutations in the protease gene, the use of enfuvirtide (T20), and the TPV phenotypic inhibitory quotient (IQ). The role of the TPV genotypic IQ (gIQ) has not yet been fully investigated. The aim of our study was to evaluate the relationship between the TPV gIQ and the VR at 48 weeks to TPV-based salvage regimens. Patients placed on regimens containing two nucleoside reverse transcriptase inhibitors plus TPV-RTV 500/200 mg twice a day with or without T20 were prospectively studied. Regular follow-up was performed over the study period. VR, considered a viral load (VL) decrease of >1 log unit and/or the achievement of <50 copies/ml with no VL rebound of >0.5 log unit compared to the maximal VL decrease at week 48, was assessed. Thirty-eight patients who had received multiple drugs were included. At week 48 the VL decrease was ؊1.48 (interquartile range [IQR], ؊2.88 to ؊0.48), 15 patients (39.5%) had VLs of <50 copies/ml, and the CD4 ؉ cell count increase was 37 cells/mm 3 (IQR, ؊30 to ؉175). Twenty subjects (52.6%) achieved VRs. The TPV gIQ and optimized background score (OBS) were independently associated with higher VL decreases. The TPV gIQ and OBS were also independent predictors of a VR at week 48. TPV gIQ and OBS cutoff values of 14,500 and 2, respectively, were associated with a higher rate of VR. The TPV gIQ was shown to be able to predict the VR at 48 weeks to TPV-containing salvage regimens better than the TPV trough concentration or TPV-associated mutations alone. A possible TPV gIQ cutoff value of 14,500 for reaching a VR at week 48 was suggested. Further studies are needed in order to evaluate the calculation of TPV gIQ as a new tool for the optimization of TPV-based salvage therapy.Tipranavir (TPV) is a nonpeptidic protease inhibitor with potent in vitro activity against most human immunodeficiency virus (HIV) type 1 (HIV-1) strains resistant to other protease inhibitors (PIs) (1,14,15). In vitro data have shown that resistance to TPV develops slowly (5). When TPV is coadministered with ritonavir (RTV) as a booster, TPV has been shown to have potent antiviral activity in multidrug-experienced patients (3,6,9,12). In the RESIST-1 and the RESIST-2 studies, the efficacy and safety of TPV-RTV (500 mg/200 mg twice daily) in 1,509 highly treatment-experienced HIV-1-positive patients were assessed. Analysis at 48 weeks showed that the TPV-RTV-containing regimens significantly improved the immune and virological responses (VRs) compared to the responses to an RTV-boosted comparator PI plus an optimized background (OB) regimen (3,6,8).Different factors have been found to be associated with the virological and immunological responses: a lower viral load (VL) at the baseline, the use of enfuvirtide (T20) as a part of the OB regimen, the presence of two or more active drugs in the OB regimen (OB score [OBS], Ն2) (3,6,8), and the baseline numbers of specific TPV-associated resistance mu...

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“…In clinical studies with healthy volunteers and HIV-infected patients, TPV pharmacokinetic parameters, including the steady-state trough concentration, the area under the concentration-time curve (AUC) for plasma, the maximum concentration in plasma during the steady state (C max ), and the apparent terminal half-life (t 1/2 ), were substantially improved with the concomitant administration of ritonavir (RTV) (8,9). Since RTV strongly inhibits cytochrome P450 3A4 (CYP3A4) (5), the boosted levels of TPV in plasma with the coadministration of TPV and RTV (TPV/r) indicate that the metabolism of TPV occurs via the cytochrome P450 (CYP450) pathway (8,9).…”

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“…Since RTV strongly inhibits cytochrome P450 3A4 (CYP3A4) (5), the boosted levels of TPV in plasma with the coadministration of TPV and RTV (TPV/r) indicate that the metabolism of TPV occurs via the cytochrome P450 (CYP450) pathway (8,9). Phase II studies have also demonstrated that TPV is an inducer of CYP450 metabolism or intestinal P glycoprotein efflux, thereby lowering systemic RTV concentrations when administered with RTV (8,11,14). Clinical studies with healthy volunteers and HIV-infected patients have evaluated potential drug interactions of TPV/r and established that no TPV dose adjustments are required when TPV/r is administered in conjunction with other commonly employed antiretroviral agents (13; F. D. Goebel, J. P. Sabo The purpose of the present study was to characterize the pharmacokinetic and metabolite profiles of TPV when administered with RTV.…”

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confidence: 99%

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

Chen¹,

Sabo²,

Philip³

et al. 2007

Antimicrob Agents Chemother

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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 Ci of [ 14 C]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 [ 14 C]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.

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

Abstract: This phase 1 study demonstrated that RTV-boosted TPV achieves concentrations that are expected to be effective in treating drug-experienced patients.

Cited by 58 publications

References 15 publications

Metabolism of novel anti-HIV agent 3-cyanomethyl-4-methyl-DCK by human liver microsomes and recombinant CYP enzymes

Metabolism of novel anti-HIV agent 3-cyanomethyl-4-methyl-DCK by human liver microsomes and recombinant CYP enzymes

Tipranavir (TPV) Genotypic Inhibitory Quotient Predicts Virological Response at 48 Weeks to TPV-Based Salvage Regimens

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

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