TABLE 3 - uploaded by Yanping Mao
Content may be subject to copyright.
Source publication
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 microCi of [(14)C...
Context in source publication
Context 1
... mean morning trough TPV concentrations from day 8 through day 15 averaged 18.2 M (range, 16.6 to 21.9 M). The calculated pharmacokinetic parameters for TPV are shown in Table 2, and those for total radioactivity are pre- sented in Table 3. Using noncompartmental analyses, the me- dian T max was calculated as 3.0 h (range, 1.5 to 5.0 h), with a median normalized C max of 83.56 M (range, 67.87 to 128.31 M) and a median normalized C 12h of 20.41 M (range, 6.29 to 65.46 M). ...
Citations
... The α-pyrones are six-membered cyclic unsaturated esters that share chemical and physical properties reminiscent to alkene and aromatic compound. These compounds occur abundantly in naturally occurring molecules and are responsible for vast range of biological activities including antibacterial, antifungal, neurotoxic, and phytotoxic properties (Dickinson, 1993;McGlacken and Fairlamb, 2005) and plant growth-regulating (Kobayashi et al., 1994;Tsuchiya et al., 1997) antitumor (Suzuki et al., 1997;Kondoh et al., 1999), and HIV protease-inhibiting activities (Thaisrivongs et al., 1996;Turner et al., 1998;Chen et al., 2007). ...
... There is little clinical evidence about what should be the regimen of choice and its adequate dosage in CKD patients 7,8,28,252,253,264,274,276,281,[292][293][294][295][296] . Nevertheless, a series of general recommendations are summarized in Table 20. ...
... NNRTIs, PIs, INSTI and fusion inhibitors do not require a dose adjustment in patients with renal function deterioration 7,8,28,252,253,264,274,276,281,[292][293][294][295][296] . In these patients, fixed-dose drug combinations must be avoided due to drug dosage difficulties. ...
... However, on chronic administration of the PIs, which are now almost always co-administered with ritonavir (RTV), the role of biliary excretion of the PIs may be even greater due to CYP3A inactivation [12]. Indeed, this is observed with tipranavir (TPV) after chronic administration of TPV/RTV [13]. Therefore, the role of hepatic transporters could become more significant in the hepatic disposition of PIs under chronic administration of PIs and/or RTV-boosted PI regimen. ...
Although HIV protease inhibitors (PIs) produce profound metabolic interactions through inactivation/inhibition of CYP3A enzymes, their role as victims of transporter-based drug-drug interactions (DDIs) is less well understood. Therefore, we investigated if the PIs, nelfinavir (NFV), ritonavir (RTV), lopinavir (LPV), or amprenavir (APV) were transported into sandwich-cultured human hepatocytes (SCHH), and whether OATPs contributed to this transport. Our findings showed that except for (3) H-APV, no significant decrease in the total hepatocyte accumulation of the (3) H-PIs was detected in the presence of the corresponding unlabeled PI, indicating that the uptake of the other PIs was not mediated. Further, hepatocyte biliary efflux studies using (3) H-APV and unlabeled APV confirmed this decrease to be due to inhibition of sinusoidal influx transporter(s) and not the canalicular efflux transporters. Moreover, this sinusoidal transport of APV was not OATP-mediated. Our results indicate the hepatic uptake of NFV, RTV, or LPV was primarily mediated by passive diffusion. APV's hepatic uptake was mediated by an unidentified sinusoidal transporter(s). Therefore, NFV, RTV or LPV will not be victims of DDIs involving inhibition of hepatic influx transporters; however, the disposition of APV may be affected if its sinusoidal transport is inhibited. Copyright © 2012 John Wiley & Sons, Ltd.
... Coadministration of tadalafil with TPV/r 500/200 mg resulted in a 2.3-fold increase in tadalafil exposure with first-dose TPV/r and no change in tadalafil exposure with steady-state TPV/r. The clinical implications of these results indicate that if tadalafil is used within the first days of TPV/r treatment when ritonavir exposure is highest [2,7,8], then the lowest dose of tadalafil should be administered. However, after 7-10 days of TPV/r dosing, steady-state for TPV/r is achieved [1], ritonavir exposure is lower, and the recommended dose of tadalafil may be used. ...
This study evaluated the effects of single-dose administration and steady-state concentrations of tipranavir 500 mg and ritonavir 200 mg (TPV/r) combination on the pharmacokinetics of tadalafil 10 mg (TAD) in an open-label study. Seventeen healthy male volunteers received sequential dosing of the studied product: TAD (day 1) alone in a single dose for 7 days followed by TAD (day 8) in a single dose with TPV/r (500/200 mg twice daily, days 8-18). Pharmacokinetic parameters were determined in a noncompartmental analysis. The geometric mean ratio and 90% confidence interval were used to evaluate drug interactions. The effect of a single dose of TAD on the pharmacokinetics of TPV/r resulted in a small decrease in exposure after either first-dose or steady-state TPV/r (geometric mean ratios [90% confidence interval]: area under the concentration-time curve, 0.85 [0.74-0.97]). In contrast, coadministration of TAD exposure was increased significantly (2.33 [2.02-2.69]) when administered with the first dose of TPV/r but not when TPV/r steady state was reached (1.01 [0.83-1.21]). Antiretroviral activity may not be reduced, but the dose of TAD should be reduced at the start of TPV/r therapy and then a full dose can be resumed after steady state is reached.
... In patients with ESRD, appropriate dose reduction is warranted for antiretrovirals that are eliminated mainly via the kidney, with additional doses given after hemodialysis for those drugs that are readily removed by dialysis. There is little clinical evidence on the dosage of antiretrovirals in ESRD patients, [78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93] but some general recommendations have been made. A summary of these recommendations is provided in Table 6. ...
... Dose adjustment for maraviroc depends on coadministered drugs. [78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93] Based on the information presented above, the ideal cART for ART-naive patients undergoing dialysis is a regimen containing abacavir (if the patient has no history of cardiovascular risk and a plasma RNA viral load of o100,000 copies/ml) 81 or tenofovir and lamivudine/emtricitabine combined with a third drug that can be efavirenz, a ritonavir-boosted protease inhibitor, or raltegravir. In patients with effective cART and NRTI side effects, the cART regimen could be simplified to monotherapy with lopinavir/ ritonavir or darunavir/ritonavir [94][95][96] or a ritonavir-boosted protease inhibitor with raltegravir. ...
The prognosis of human immunodeficiency virus (HIV) infection has improved in recent years with the introduction of antiretroviral treatment. While the frequency of AIDS-defining events has decreased as a cause of death, mortality from non-AIDS-related events including end-stage renal diseases has increased. The etiology of chronic kidney disease is multifactorial: immune-mediated glomerulonephritis, HIV-associated nephropathy, thrombotic microangiopathies, and so on. HIV infection is no longer a contraindication to transplantation and is becoming standard therapy in most developed countries. The HIV criteria used to select patients for renal transplantation are similar in Europe and North America. Current criteria state that prior opportunistic infections are not a strict exclusion criterion, but patients must have a CD4+ count above 200 cells/mm(3) and a HIV-1 RNA viral load suppressible with treatment. In recent years, more than 200 renal transplants have been performed in HIV-infected patients worldwide, and mid-term patient and graft survival rates have been similar to that of HIV-negative patients. The main issues in post-transplant period are pharmacokinetic interactions between antiretrovirals and immunosuppressants, a high rate of acute rejection, the management of hepatitis C virus coinfection, and the high cardiovascular risk after transplantation. More studies are needed to determine the most appropriate antiretroviral and immunosuppressive regimens and the long-term outcome of HIV infection and kidney graft.
... Metabolites were identified using a flow scintillation analyzer in conjunction with liquid chromatography-tandem mass spectrometry. The most abundant metabolite in feces was identified as an oxidation metabolite, whereas a TPV glucuronide metabolite was identified in urine (Chen et al., 2007b). In these two studies, two monohydroxylation metabolites, a dehydrogenation metabolite, and a glucuronide conjugate metabolite of TPV were observed (Chen et al., 2007b;Macha et al., 2007). ...
... The most abundant metabolite in feces was identified as an oxidation metabolite, whereas a TPV glucuronide metabolite was identified in urine (Chen et al., 2007b). In these two studies, two monohydroxylation metabolites, a dehydrogenation metabolite, and a glucuronide conjugate metabolite of TPV were observed (Chen et al., 2007b;Macha et al., 2007). However, neither the contributions of P450s in TPV metabolism nor the effects of RTV on TPV metabolism are clear. ...
... This finding is in accordance with previous studies using radiolabeled TPV. In previous studies, two monohy-droxylated metabolites, one dehydrogenated metabolite, and one glucuronide-conjugated metabolite have been reported (Chen et al., 2007b;Macha et al., 2007). In these reports, one hydroxylation took place in a benzyl group, and the other hydroxylation occurred in a trifluoromethyl-substituted pyridinyl ring. ...
Tipranavir (TPV) is the first nonpeptidic protease inhibitor used for the treatment of drug-resistant HIV infection. Clinically, TPV is coadministered with ritonavir (RTV) to boost blood concentrations and increase therapeutic efficacy. The mechanism of metabolism-mediated drug interactions associated with RTV-boosted TPV is not fully understood. In the current study, TPV metabolism was investigated in mice using a metabolomic approach. TPV and its metabolites were found in the feces of mice but not in the urine. Principal component analysis of the feces metabolome uncovered eight TPV metabolites, including three monohydroxylated, three desaturated, one dealkylated, and one dihydroxylated. In vitro study using human liver microsomes recapitulated five TPV metabolites, all of which were suppressed by RTV. CYP3A4 was identified as the primary enzyme contributing to the formation of four TPV metabolites (metabolites II, IV, V, and VI), including an unusual dealkylated product arising from carbon-carbon bond cleavage. Multiple cytochromes P450 (2C19, 2D6, and 3A4) contributed to the formation of a monohydroxylated metabolite (metabolite III). In vivo, RTV cotreatment significantly inhibited eight TPV metabolic pathways. In summary, metabolomic analysis revealed two known and six novel TPV metabolites in mice, all of which were suppressed by RTV. The current study provides solid evidence that the RTV-mediated boosting of TPV is due to the modulation of P450-dependent metabolism.
... 18 Co-administration of ritonavir leads to a 4-fold rise of Cmax, a 48-fold rise of Cmin and a 9 times greater exposure (AUC: area under the curve). 17,19 As a result, effective plasma/serum tipranavir concentrations can be achieved with a twice-daily dose administation. Ritonavir has a boosting effect on the plasma concentrations of tipranavir through inhibition of hepatic (and intestinal) cytochrome P450 (CYP) 4A and inhibition of the P-glycoprotein (P-gp) efflux pump. ...
Tipranavir (TPV) is a selective nonpeptidic HIV-1 protease inhibitor (PI) which is used in the treatment of treatment-experienced adults with HIV-1 infection. Tipranavir is administered orally twice daily in combination with low-dose ritonavir. The durable efficacy of tipranavir, in combination with low-dose ritonavir (tipranavir/ritonavir 500 mg/200 mg twice daily), has been demonstrated in well designed trials in treatment-experienced adults infected with multidrug-resistant strains of HIV-1. In treatment-experienced adults with HIV-1 infection receiving an optimized background regimen, viral suppression was greater and immunological responses were better with regimens containing tipranavir/ritonavir than with comparator ritonavir-boosted PI-containing regimens. The efficacy appeared to be more marked in patients receiving two fully active drugs in the regimen, with the combination of tipranavir/ritonavir and enfuvirtide (for the first time) appearing to be the most successful. Although tipranavir is generally well tolerated, clinical hepatitis and hepatic decompensation, and intracranial hemorrhage have been associated with the drug. Tipranavir also has a complex drug interaction profile. Thus, tipranavir, administered with ritonavir, is an effective treatment option for use in the combination therapy of adults with HIV-1 infection who have been previously treated with other antiretroviral drugs.
Three novel SEK15-derived polyketides, strepolyketides A-C (1-3), and the known SEK15 (4) were identified from Streptomyces sp. HN2A53. Their structures were established by comprehensive 1D and 2D NMR spectroscopic analysis and HRESIMS data. Compounds 2-3 were the unique dimers of SEK15. Biological evaluation of these compounds showed that compounds 2-4 showed moderate inhibitory activity against influenza virus neuraminidase (NA) in vitro
Eight new α-pyrones 1-8 and three known α-pyrones 9-11 were isolated from three marine-derived Nocardiopsis strains SCSIO 10419, SCSIO 04583, and SCSIO KS107. The structures of compounds 1-8 were elucidated by comprehensive spectral analyses. The absolute configurations of 4-deoxyphomapyrone C (1), 4-deoxy-11-hydroxyphomapyrone C (3), 4-deoxy-7R-hydroxyphomapyrone C (5), and phomapyrone C (11) were determined by TDDFT-ECD calculations for the solution conformers, which revealed that the conformation of the side chain was decisive for the sign of the characteristic high-wavelength ECD transition. (-)-4-Deoxy-8-hydroxyphomapyrone C (4) was isolated from SCSIO 10419 and was deduced as a diastereomeric mixture containing (8S)- and (8R)-4-deoxy-8-hydroxyphomapyrone C in a ratio of 2.6:1 (8R:8S), by chiral-phase HPLC analysis and Mosher's ester analysis. Interestingly, 7-hydroxymucidone (9) was isolated from both SCSIO 04583 and SCSIO KS107, as an enantiomeric mixture containing (7S)-hydroxymucidone (major in 9 from SCSIO 04583) and (7R)-hydroxymucidone (major in 9 from SCSIO KS107). α-Pyrones 3-5 were identified as three isomers of phomapyrone C (11) with diverse hydroxy substitutions. α-Pyrones 10-hydroxymucidone (6), 4-hydroxymucidone (8), and 9, differed in the position of the hydroxy group. Several α-pyrones exhibited moderate growth inhibitory activity against Micrococcus luteus and Bacillus subtilis.
In this update, antiretroviral therapy (ART) is recommended for all patients infected by type 1 human immunodeficiency virus (HIV-1). The strength and grade of the recommendation vary depending on the CD4+ T-lymphocyte count, the presence of opportunistic infections or comorbid conditions, age, and the efforts to prevent the transmission of HIV. The objective of ART is to achieve an undetectable plasma viral load (PVL). Initial ART should comprise three drugs, namely, two nucleoside reverse transcriptase inhibitors (NRTI) and one drug from another family. Three of the recommended regimens, all of which have an integrase strand transfer inhibitor (INSTI) as the third drug, are considered a preferred regimen; a further seven regimens, which are based on an INSTI, an non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor boosted with ritonavir (PI/r), are considered alternatives. The reasons and criteria for switching ART are presented both for patients with an undetectable PVL and for patients who experience virological failure, in which case the rescue regimen should include three (or at least two) drugs that are fully active against HIV. The specific criteria for ART in special situations (acute infection, HIV-2 infection, pregnancy) and comorbid conditions (tuberculosis and other opportunistic infections, kidney disease, liver disease, and cancer) are updated. © 2015 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica.
