Pharmacokinetic Interaction between Maraviroc and Fosamprenavir-Ritonavir: an Open-Label, Fixed-Sequence Study in Healthy Subjects

Vourvahis, Manoli; Plotka, Anna; Costa, Laure Mendes da; Fang, Annie; Heera, Jayvant

doi:10.1128/aac.01098-13

Cited by 7 publications

(5 citation statements)

References 18 publications

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“… 92 Fosamprenavir (FPV), an APV pro-drug, is used as a slow-release version of APV. In a treatment regimen including FPV, RTV, and MVC, MVC AUC and Cmax increased by 249% and 152%, respectively; 94 APV AUC and Cmax decreased by 35% and 34%, respectively; 94 RTV AUC and Cmax decreased by 34% and 39%, respectively. 94 While FPV/RTV increasing MVC concentrations is not surprising, since both are CYP3A4 inhibitors, the mechanisms of MVC reducing RTV and FPV concentrations are not known.…”

Section: Mvc Drug–drug Interactionsmentioning

confidence: 99%

“…In a treatment regimen including FPV, RTV, and MVC, MVC AUC and Cmax increased by 249% and 152%, respectively; 94 APV AUC and Cmax decreased by 35% and 34%, respectively; 94 RTV AUC and Cmax decreased by 34% and 39%, respectively. 94 While FPV/RTV increasing MVC concentrations is not surprising, since both are CYP3A4 inhibitors, the mechanisms of MVC reducing RTV and FPV concentrations are not known. This may involve protein-binding displacement, which is associated with increase in unbound FPV and RTV ready to be metabolized.…”

Section: Mvc Drug–drug Interactionsmentioning

confidence: 99%

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Maraviroc: a review of its use in HIV infection and beyond

Woollard¹,

Kanmogne²

2015

DDDT

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The human immunodeficiency virus-1 (HIV-1) enters target cells by binding its envelope glycoprotein gp120 to the CD4 receptor and/or coreceptors such as C-C chemokine receptor type 5 (CCR5; R5) and C-X-C chemokine receptor type 4 (CXCR4; X4), and R5-tropic viruses predominate during the early stages of infection. CCR5 antagonists bind to CCR5 to prevent viral entry. Maraviroc (MVC) is the only CCR5 antagonist currently approved by the United States Food and Drug Administration, the European Commission, Health Canada, and several other countries for the treatment of patients infected with R5-tropic HIV-1. MVC has been shown to be effective at inhibiting HIV-1 entry into cells and is well tolerated. With expanding MVC use by HIV-1-infected humans, different clinical outcomes post-approval have been observed with MVC monotherapy or combination therapy with other antiretroviral drugs, with MVC use in humans infected with dual-R5- and X4-tropic HIV-1, infected with different HIV-1 genotype or infected with HIV-2. This review discuss the role of CCR5 in HIV-1 infection, the development of the CCR5 antagonist MVC, its pharmacokinetics, pharmacodynamics, drug–drug interactions, and the implications of these interactions on treatment outcomes, including viral mutations and drug resistance, and the mechanisms associated with the development of resistance to MVC. This review also discusses available studies investigating the use of MVC in the treatment of other diseases such as cancer, graft-versus-host disease, and inflammatory diseases.

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Section: Mvc Drug–drug Interactionsmentioning

confidence: 99%

Section: Mvc Drug–drug Interactionsmentioning

confidence: 99%

Maraviroc: a review of its use in HIV infection and beyond

Woollard¹,

Kanmogne²

2015

DDDT

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“…Maraviroc was approved based on the MOTIVATE trials comprised of 85% individuals with European ancestry (Gulick et al, 2008) and most previous maraviroc pharmacokinetic studies were conducted in participants with European ancestry, with the median percentage of participants with European ancestry at 78.5% (Abel et al, 2008a,b,c,d,f;Chan et al, 2008;Pozniak et al, 2008;Dumond et al, 2009;Andrews et al, 2010;Ramanathan et al, 2010;Brown et al, 2011;Kakuda et al, 2011;Gruber et al, 2013;Mora-Peris et al, 2013;Taiwo et al, 2013;Vourvahis et al, 2013). A few studies compared maraviroc concentrations in individuals with African ancestry with individuals with European ancestry and concluded that there were no differences or higher concentrations in individuals with African ancestry (FDA, 2007;Okoli et al, 2012), which may be due to the use of CYP3A inhibitors such as ritonavir in the optimized background therapy in which CYP3A5 activity may have been inhibited in individuals who are carrying CYP3A5*1 allele.…”

Section: Discussionmentioning

confidence: 99%

CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers

Fuchs

Hendrix

et al. 2014

Drug Metab Dispos

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CYP3A5 plays a prominent role in the metabolism of maraviroc, an approved drug for human immunodeficiency virus (HIV)-1 treatment and a candidate for HIV-1 prevention. We studied the effect of the CYP3A5 genotype on pharmacokinetics of maraviroc and a primary CYP3A5-dependent metabolite of maraviroc denoted as metabolite 1 (M1). Volunteers were screened for health status and CYP3A5 genotype (wild-type allele *1 and dysfunctional alleles *2, *3, *6, and *7) to obtain 24 evaluable subjects in three groups (n = 8 each): homozygous dysfunctional (two dysfunctional alleles), heterozygous (one *1 allele and one dysfunctional allele), and homozygous wild-type (two *1 alleles). Subjects received 300 mg maraviroc orally followed by blood collection for 32 hours. The homozygous wild-type group exhibited lower mean plasma maraviroc concentrations at almost all sampling times. The median (interquartile range) maraviroc area under the plasma concentration-time curves from time 0 to infinity (AUC 0-inf ) were 2099 (1422-2568) ng×h/ml, 1761 (931-2640) ng×h/ml, and 1238 (1065-1407) ng×h/ml for the homozygous dysfunctional, heterozygous, and homozygous wildtype groups, respectively. The homozygous wild-type group had 41% lower maraviroc AUC 0-inf and 66% higher apparent clearance compared with the homozygous dysfunctional group (P = 0.02). The AUC 0-inf ratios of maraviroc to M1 in heterozygous and homozygous wild-type subjects were lower by 51 and 64% relative to the homozygous dysfunctional group, respectively (P < 0.001). In conclusion, the lower maraviroc concentrations in the homozygous wild-type group indicate that maraviroc may be underdosed in people homozygous for the CYP3A5*1 allele, including almost onehalf of African Americans.

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“…In the presence versus absence of ketoconazole 400 mg once daily for 9 days, maraviroc AUC ratio (90% confidence interval [CI]) was 5.0‐fold (4.0‐6.3) . Except for saquinavir/ritonavir, in the presence versus absence of protease inhibitors maraviroc AUC was increased <5‐fold (Figure ) . The effects of ketoconazole and ritonavir on CYP3A substrates triazolam, alfentanil, and avanafil were similar, with substrate AUC increased >9‐fold (Table ) …”

Section: Resultsmentioning

confidence: 98%

“…33 Except for saquinavir/ritonavir, in the presence versus absence of protease inhibitors maraviroc AUC was increased <5-fold (Figure 3). [33][34][35][36] The effects of ketoconazole and ritonavir on CYP3A substrates triazolam, alfentanil, and avanafil were similar, with substrate AUC increased >9-fold (Table 2). [37][38][39][40][41]…”

Section: Effect Of Protease Inhibitors On the Pk Of Cyp3a Substratesmentioning

confidence: 97%

Dosing Recommendations for Quetiapine When Coadministered With HIV Protease Inhibitors

Sampson

Cao

Gish

et al. 2018

The Journal of Clinical Pharma

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Although current quetiapine labeling recommends that its dosage should be lowered 6‐fold when coadministered with strong cytochrome P450 (CYP)3A inhibitors, a reported case of coma in a patient receiving quetiapine with lopinavir and ritonavir prompted the reevaluation of labeling recommendations for the dosing of quetiapine when coadministered with human immunodeficiency virus (HIV) protease inhibitors. Literature and database (FDA Adverse Event Reporting System and United States Symphony Health Solutions’ Integrated Dataverse Database) searches allowed us to identify cases of coma and related adverse events involving the coadministration of quetiapine and HIV protease inhibitors and to estimate the frequency of concomitant use. Literature review and physiologically based pharmacokinetic modeling allowed us to estimate the potential for CYP3A inhibition to contribute to adverse events related to HIV protease inhibitor–quetiapine coadministration. We identified excess sedation following coadministration of quetiapine and an HIV protease inhibitor in 3 reports without obvious confounders. In prescription claims data, 0.4% of quetiapine patients were dispensed a concurrent ritonavir prescription. The quetiapine dose was not reduced on ritonavir initiation in 90% of therapy episodes. Available data indicate to us that all HIV protease inhibitors combined with ritonavir are likely to be strong CYP3A inhibitors. We predicted that ritonavir would increase quetiapine exposure comparable to the strong CYP3A inhibitor ketoconazole. The current dosing recommendations for use of quetiapine with strong CYP3A inhibitors (ie, 6‐fold lower quetiapine dose) are appropriate and should be followed when quetiapine is coadministered with HIV protease inhibitors.

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Pharmacokinetic Interaction between Maraviroc and Fosamprenavir-Ritonavir: an Open-Label, Fixed-Sequence Study in Healthy Subjects

Cited by 7 publications

References 18 publications

Maraviroc: a review of its use in HIV infection and beyond

Maraviroc: a review of its use in HIV infection and beyond

CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers

Dosing Recommendations for Quetiapine When Coadministered With HIV Protease Inhibitors

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