Effect of posaconazole on the pharmacokinetics of fosamprenavir and vice versa in healthy volunteers

Brüggemann, Roger J. M.; Luin, Matthijs van; Colbers, E.P.H.; Dungen, Myrthe W. van den; Pharo, Cristina; Schouwenberg, B.J.J.W.; Burger, David M.

doi:10.1093/jac/dkq280

Cited by 16 publications

(11 citation statements)

References 25 publications

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“…Pharmacokinetic, demographic, and relevant clinical data from two posaconazole studies in healthy volunteers and in patients receiving a posaconazole oral suspension for the prophylaxis or treatment of fungal infections were available for analysis (6,21). Information on study design, population, pharmacokinetic data, and participant demographics is included in Table 1.…”

Section: Methodsmentioning

confidence: 99%

“…Information on study design, population, pharmacokinetic data, and participant demographics is included in Table 1. Further details on these studies have been described previously (6,21).…”

Section: Methodsmentioning

confidence: 99%

“…The structural pharmacokinetic model was developed using a stepwise approach. The base pharmacokinetic model was initially developed using the richly sampled concentration-time data (study 1, healthy volunteer data [21]), with sparsely sampled data (study 2, patient data [6]), and then incorporated into the model with appropriate goodness-of-fit testing.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis

Dolton

Brüggemann

Burger

et al. 2014

Antimicrob Agents Chemother

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c Posaconazole oral suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterize the pharmacokinetics of posaconazole in adults and investigate factors that influence posaconazole pharmacokinetics byusing a population pharmacokinetic approach. Nonlinear mixed-effects modeling was undertaken for two posaconazole studies in patients and healthy volunteers. The influences of demographic and clinical characteristics, such as mucositis, diarrhea, and drugdrug interactions, on posaconazole pharmacokinetics were investigated using a stepwise forward inclusion/backwards deletion procedure. A total of 905 posaconazole concentration measurements from 102 participants were analyzed. A one-compartment pharmacokinetic model with first-order oral absorption with lag time and first-order elimination best described posaconazole pharmacokinetics. Posaconazole relative bioavailability was 55% lower in patients who received posaconazole than in healthy volunteers. Coadministration of proton pump inhibitors (PPIs) or metoclopramide, as well as the occurrence of mucositis or diarrhea, reduced posaconazole relative bioavailability by 45%, 35%, 58%, and 45%, respectively, whereas concomitant ingestion of a nutritional supplement significantly increased bioavailability (129% relative increase). Coadministration of rifampin or phenytoin increased apparent posaconazole clearance by more than 600%, with a smaller increase observed with fosamprenavir (34%). Participant age, weight, or sex did not significantly affect posaconazole pharmacokinetics. Posaconazole absorption was reduced by a range of commonly coadministered medicines and clinical complications, such as mucositis and diarrhea. Avoidance of PPIs and metoclopramide and administration with food or a nutritional supplement are effective strategies to increase posaconazole absorption.

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Section: Methodsmentioning

confidence: 99%

“…Information on study design, population, pharmacokinetic data, and participant demographics is included in Table 1. Further details on these studies have been described previously (6,21).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis

Dolton

Brüggemann

Burger

et al. 2014

Antimicrob Agents Chemother

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“…For instance, pediatrics, pregnancy, aging, hepatic impairment, and obesity or cachexia may be associated with changes in pharmacokinetic parameters that can affect absorption, metabolism, and clearance of drugs. 143 Therapeutic drug monitoring may also be useful in evaluating suspected drug interactions, malabsorption, toxicity of certain antiretrovirals, virologic failure, and use of unboosted protease inhibitors or unconventional regimens that may be associated with a risk of suboptimal trough concentrations. 144 Therapeutic drug monitoring can also be a valuable clinical tool, especially when combined with other important treatment considerations as part of overall clinical management of a patient.…”

Section: Therapeutic Drug Monitoringmentioning

confidence: 99%

Role of the Pharmacist in Caring for Patients with HIV/AIDS: Clinical Practice Guidelines

Tseng

Foisy

Hughes

et al. 2012

CJHP

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“…Ritonavir is an inducer and inhibitor of CYP3A4, is an inducer of UGT1A1, and has a time-dependent inhibition effect followed by an induction effect on P-glycoprotein (9). Fosamprenavir, the prodrug for amprenavir (APV), has been demonstrated to induce enzymatic activity of UGT1A1 and to induce or inhibit CYP3A4 enzymes (10,11). Thus, a study to evaluate its impact on DTG exposure was warranted.…”

mentioning

confidence: 99%

Effect of Fosamprenavir-Ritonavir on the Pharmacokinetics of Dolutegravir in Healthy Subjects

Song

Borland

Chen

et al. 2014

Antimicrob Agents Chemother

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objective of this open-label, 2-period, single-sequence study was to evaluate the effect of fosamprenavir-ritonavir (FPV-RTV) on the steady-state plasma pharmacokinetics of DTG. Twelve healthy subjects received 50 mg DTG once daily for 5 days (period 1), followed by 10 days of 50 mg DTG once daily in combination with 700/100 mg FPV-RTV every 12 h (period 2). All doses were administered in the fasting state. Serial pharmacokinetic samples for DTG and amprenavir and safety assessments were obtained throughout the study. Noncompartmental pharmacokinetic analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated for within-subject treatment comparison. Fosamprenavir-ritonavir decreased the DTG area under the concentration-time curve, maximum concentration in plasma, and concentration in plasma at the end of the dosing interval by 35%, 24%, and 49%, respectively. Both DTG and DTG with FPV-RTV were well tolerated; no subject withdrew because of adverse events. The most frequently reported drug-related adverse events were rash, abnormal dreams, and nasopharyngitis. The modest decrease in DTG exposure when it was coadministered with FPV-RTV is not considered clinically significant, and DTG dose adjustment is not required with coadministration of FPV-RTV in INI-naive patient populations on the basis of established "no-effect" boundaries of DTG. In the INI-resistant population, as a cautionary measure, alternative combinations that do not include FPV-RTV should be considered. (This study has been registered at ClinicalTrials.gov under identifier NCT01209065.) T he integrase inhibitor (INI) class of antiretroviral drugs has proven to be a valuable addition to treatment strategies for the management of HIV. Good tolerability and lack of cross-resistance to other classes of antiretroviral therapy have contributed to the use of INIs in the antiretroviral regimen for both treatmentexperienced and treatment-naive patients (1). Dolutegravir (DTG) is an unboosted, once-daily [QD] INI that can be differentiated from previous INIs (e.g., raltegravir [RAL] and elvitegravir) by its resistance profile and predictable pharmacokinetics (PK) with low to moderate intersubject variability (2, 3). Drugdrug interaction studies between ritonavir (RTV)-boosted protease inhibitors (i.e., tipranavir [TPV], darunavir, lopinavir, and atazanavir) and DTG have been conducted previously to evaluate changes in the plasma exposure to DTG. These studies have reported modest changes in DTG PK, and dosage adjustments are not required when administered with most commonly used RTVboosted protease inhibitors, except for TPV-RTV (4-6).Dolutegravir is metabolized primarily via uridine 5=-diphosphoglucuronosyltransferase-1A1 (UGT1A1), although cytochrome P450 3A4 (CYP3A4) has a minor role (10% to 15%) in the process, and it is a substrate of the transport protein P-glycoprotein (7,8). Therefore, drugs that induce or inhibit these metabolic pathways may affect the plasma exposure of DTG. Dolutegravir does not in...

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Effect of posaconazole on the pharmacokinetics of fosamprenavir and vice versa in healthy volunteers

Abstract: Unboosted fosamprenavir should not be used concomitantly with posaconazole.

Cited by 16 publications

References 25 publications

Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis

Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis

Role of the Pharmacist in Caring for Patients with HIV/AIDS: Clinical Practice Guidelines

Effect of Fosamprenavir-Ritonavir on the Pharmacokinetics of Dolutegravir in Healthy Subjects

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