Pharmacokinetics and Bioavailability of an Integrase and Novel Pharmacoenhancer-Containing Single-Tablet Fixed-Dose Combination Regimen for the Treatment of HIV

German, Polina; Warren, David R.; West, Steve; Hui, James; Kearney, Brian P.

doi:10.1097/qai.0b013e3181eb376b

Cited by 82 publications

(69 citation statements)

References 18 publications

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“…Exposures of efavirenz and emtricitabine (AUC s , C max , and C s ), and tenofovir (AUC s and C s ) were unchanged (90 % CIs within 70-143 %). Tenofovir C max was modestly increased (25 %) and does not necessitate dose modification as the increase in C max is less than that observed on co-administration of tenofovir disoproxil fumarate and elvitegravir/cobicistat (30 % increase in tenofovir C max ) which did not necessitate dose adjustment [26]. Sofosbuvir and GS-331007 AUC ?…”

Section: Non-nucleoside Reverse Transcriptase Inhibitorsmentioning

confidence: 87%

Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir

et al. 2015

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Sofosbuvir (SOVALDI(®)), a potent, once-daily, orally administered nucleotide analog prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase is approved in the USA, EU, Canada, and other regions for the treatment of HCV infection as a component of an antiviral treatment regimen. Sofosbuvir undergoes intracellular activation to form GS-461203 (active triphosphate, not detected in plasma), and ultimately the inactive, renally eliminated metabolite GS-331007. GS-331007 was identified as the primary analyte of interest for clinical pharmacology studies as it accounted for >90 % of systemic drug-related material exposure, and provided comparable exposure-response relationships for viral kinetics as observed for sofosbuvir. GS-331007 and sofosbuvir exhibit linear pharmacokinetics with minimal accumulation upon multiple dosing. Compared to healthy subjects, HCV-infected patients had modestly lower (39 %) GS-331007 area under the plasma concentration-time curve (AUC) and higher sofosbuvir AUC (60 %). Sofosbuvir can be administered without dose modification in HCV-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. Sofosbuvir has a low propensity for clinically significant drug interactions with common concomitant medications used by HCV-infected patients. Clinically significant alterations in GS-331007 or sofosbuvir exposures are limited to potent inducers of intestinal P-glycoprotein that may lower exposure. In HCV-infected patients, demographic variables do not significantly influence GS-331007 and sofosbuvir exposures and no consistent exposure-response relationships were observed for efficacy or safety. This review focuses on the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic-pharmacodynamic relationships of sofosbuvir, and summarizes a number of drug interaction studies with important concomitant medications commonly used by HCV-infected patients.

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Section: Non-nucleoside Reverse Transcriptase Inhibitorsmentioning

confidence: 87%

Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir

et al. 2015

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“…COBI's lack of anti-HIV activity also eliminates the potential for selection of PI resistance mutations when boosting non-HIV PI drugs (21). Clinically, COBI increases systemic levels of the CYP3A substrates midazolam and elvitegravir (EVG) to a similar extent as RTV (7,13), and coadministration with COBI allows EVG to be administered once daily (16). A fixed-dose, once-daily, single-tablet regimen that includes EVG/COBI and the nucleos(t)ide reverse transcriptase inhibitors tenofovir disoproxil fumarate and emtricitabine, colloquially known as "QUAD," has completed registrational trials, including meeting its primary endpoints in phase 3 studies (2,3,19,20).…”

mentioning

confidence: 99%

Cobicistat Boosts the Intestinal Absorption of Transport Substrates, Including HIV Protease Inhibitors and GS-7340, In Vitro

Lepist

Phan

Roy

et al. 2012

Antimicrob Agents Chemother

126

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The experimental pharmacoenhancer cobicistat (COBI), a potent mechanism-based inhibitor of cytochrome P450 3A enzymes, was found to inhibit the intestinal efflux transporters P-glycoprotein and breast cancer resistance protein. Consistent with its transporter inhibition, COBI significantly increased the absorptive flux of potential candidates for clinical coadministration, including the HIV protease inhibitors atazanavir and darunavir and the lymphoid cell-and tissue-targeted prodrug of the nucleotide analog tenofovir, GS-7340, through monolayers of Caco-2 cells in vitro.C obicistat (COBI) is being developed as a pharamacoenhancer (booster) for coformulation with drugs that are metabolized by cytochrome P450 3A (CYP3A) enzymes. Similar to ritonavir (RTV; currently used as a pharmacoenhancer of protease inhibitors [PIs] used to treat human immunodeficiency virus [HIV]), COBI is a potent mechanism-based CYP3A inhibitor, and its coadministration with CYP3A substrates can lead to desired boosting effects and unintended drug-drug interactions. COBI has been found to have a number of potentially differentiating attributes relative to RTV: (i) it has more selective CYP3A inhibition over other CYP enzymes, (ii) it has improved solubility and coformulatability, (iii) it has a reduced induction potential mediated by the pregnane X receptor (PXR; also known as the nuclear receptor subfamily 1, group 1, member 2 [NR1I2]), and (iv) it has decreased effects on adipocytes in vitro (21). COBI's lack of anti-HIV activity also eliminates the potential for selection of PI resistance mutations when boosting non-HIV PI drugs (21). Clinically, COBI increases systemic levels of the CYP3A substrates midazolam and elvitegravir (EVG) to a similar extent as RTV (7, 13), and coadministration with COBI allows EVG to be administered once daily (16). A fixed-dose, once-daily, single-tablet regimen that includes EVG/COBI and the nucleos(t)ide reverse transcriptase inhibitors tenofovir disoproxil fumarate and emtricitabine, colloquially known as "QUAD," has completed registrational trials, including meeting its primary endpoints in phase 3 studies (2,3,19,20).Inhibition of efflux transporters expressed in the intestine can serve as a secondary mechanism for a pharmacoenhancer to increase systemic exposure to coadministered drugs by increasing their absorption. P-glycoprotein (Pgp; also known as multidrug resistance protein 1 [MDR1] or ATP-binding cassette subfamily B member 1 [ABCB1]) and the breast cancer resistance protein (BCRP; also known as ATP-binding cassette subfamily G member 2 [ABCG2]), both expressed at the apical side of the small intestine, have been highlighted by regulatory agencies and in the literature as key transporters affecting xenobiotic pharmacokinetics (5, 6). In addition to the role of CYP3A enzymes in RTV boosting, HIV PIs are known to be substrates for transporters, including Pgp (11). Determination of the relative roles of transport and CYP3A inhibition in limiting HIV PI exposure is difficult due to their being sub...

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“…The first INSTI-based STR combines elvitegravir (EVG) with the pharmacokinetic enhancer cobicistat (COBI) and the NRTIs emtricitabine (FTC) and tenofovir (TFV) disoproxil fumarate (TDF) (EVG-COBI-FTC-TDF) (10). In the phase III studies of EVG-COBI-FTC-TDF, 18 of the 701 total subjects treated with EVG-COBI-FTC-TDF (2.6%) developed RAMs through 144 weeks (11)(12)(13)(14).…”

mentioning

confidence: 99%

Reduced Viral Fitness and Lack of Cross-Class Resistance with Integrase Strand Transfer Inhibitor and Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations

Andreatta

Goodman

Miller

et al. 2015

Antimicrob Agents Chemother

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T he majority of marketed antiretroviral (ARV) inhibitors for treatment of HIV-1 infection target one of three enzymes essential for viral replication: protease (PR), reverse transcriptase (RT), or integrase (IN). Initial ARV therapy recommended by the current treatment guidelines consists of a combination of three inhibitors from at least two drug classes, typically, two nucleos(t)ide RT inhibitors (NRTIs) plus a ritonavir-boosted PR inhibitor (PI), nonnucleoside RT inhibitor (NNRTI), or IN strand transfer inhibitor (INSTI) (1-5). While ARV therapy successfully suppresses viral replication in most cases, the emergence of drug resistance mutations may occur and constitutes a major limitation to long-term treatment efficacy. Resistance-associated mutations (RAMs) often accumulate during virologic failure, potentially reducing viral susceptibility to multiple drugs along with reducing viral replicative fitness. However, additional accessory mutations that may compensate for this fitness defect, with or without further diminishing drug susceptibility, can also develop within the same coding region of the target enzyme (6-9).Single-tablet regimens (STRs) can offer complete ARV therapy in a once-daily pill. The first INSTI-based STR combines elvitegravir (EVG) with the pharmacokinetic enhancer cobicistat (COBI) and the NRTIs emtricitabine (FTC) and tenofovir (TFV) disoproxil fumarate (TDF) (EVG-COBI-FTC-TDF) (10). In the phase III studies of EVG-COBI-FTC-TDF, 18 of the 701 total subjects treated with EVG-COBI-FTC-TDF (2.6%) developed RAMs through 144 weeks (11)(12)(13)(14). The most common pattern of viral resistance contained the FTC primary resistance substitution M184V in RT (RT-M184V) coupled with the EVG primary resistance substitution E92Q in IN (IN-E92Q) (8 subjects) (13-15). The TFV resistance substitution K65R in RT (RT-K65R) also occurred in combination with the M184V and E92Q substitutions in two of these cases. Clonal sequence analysis of patient-derived viral isolates revealed that these substitutions often occurred together on the same viral genomes (15). While IN-E92Q, RT-M184V, and RT-K65R have been previously characterized individually and with other substitutions in the same coding region, the impact of these three substitutions combined in the same genome on drug susceptibility or viral fitness has not been studied.Since HIV-1 IN and RT enzymes are expressed together in a polyprotein and are proximally associated in preintegration complexes, functional interplay is possible (16)(17)(18). Some evidence suggesting that mutations in RT and IN may cooperatively produce cross-class drug resistance and/or compensatory fitness effects has been presented. For example, HIV-1 site-directed mutants with certain combinations of INSTI and NNRTI resistance substitutions, such as G140S/Q148H in IN with K103N in RT, Citation Andreatta KN, Goodman DD, Miller MD, White KL. 2015. Reduced viral fitness and lack of cross-class resistance with integrase strand transfer inhibitor and nucleoside reverse transcriptase inhi...

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Pharmacokinetics and Bioavailability of an Integrase and Novel Pharmacoenhancer-Containing Single-Tablet Fixed-Dose Combination Regimen for the Treatment of HIV

Abstract: Fixed-dose combination tablet containing COBI 150 mg resulted in desired high EVG Ctau concentrations and clinically equivalent tenofovir and FTC exposures relative to currently approved individual agents and was thus selected for subsequent evaluation.

Cited by 82 publications

References 18 publications

Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir

Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir

Cobicistat Boosts the Intestinal Absorption of Transport Substrates, Including HIV Protease Inhibitors and GS-7340, In Vitro

Reduced Viral Fitness and Lack of Cross-Class Resistance with Integrase Strand Transfer Inhibitor and Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations

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