Saquinavir, nelfinavir and M8 pharmacokinetics following combined saquinavir, ritonavir and nelfinavir administration

Stocker, Hartmut; Herzmann, Christian; Breske, Antje; Kruse, Guido; Berger, M; Schulbin, Hubert; Hill, Andrew; Steinmüller, Jutta; Becker, Mark; Arastéh, Keikawus; Kurowski, Michael

doi:10.1093/jac/dkl516

Cited by 6 publications

(1 citation statement)

References 8 publications

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“…In prior pharmacokinetic studies, NFV was shown to interact with a myriad of drugs metabolized by the cytochrome P-450 group of enzymes. [34][35][36] Another limitation is the fact that we did not collect genotyping data; therefore, there is no information on possible protease inhibitor resistance.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Increased Nelfinavir Plasma Concentrations in Women During Pregnancy and Postpartum

Eke

McCormack

Best

et al. 2018

The Journal of Clinical Pharma

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This study aims to evaluate the safety, acceptability, and pharmacokinetics (PK) of an increased dose of nelfinavir (NFV) during the third trimester of pregnancy. The study was registered as part of the International Maternal Pediatric Adolescent AIDS Clinical Trials network (IMPAACT-P1026s), an ongoing multicenter prospective cohort study of antiretroviral PK during pregnancy (NCT00042289). NFV intensive PK evaluations were performed at steady state during the third trimester of pregnancy and 2-3 weeks postpartum. Plasma concentrations of NFV and its active metabolite, hydroxyltert-butylamide (M8) were measured using high-performance liquid chromatography with ultraviolet detection. A total of 18 women are included in the analysis. NFV area under the concentration-time curve (AUC) with the increased dose during the third trimester was nearly identical to the standard dose postpartum, with a geometric mean ratio for third trimester to postpartum AUC of 0.98 (90%CI 0.71-1.35). Despite the increased dose, M8 AUC was lower during the third trimester compared to postpartum (0.53, IQR [0.38-0.75]), as was the M8/NFV AUC ratio (0.51, IQR [0.42-0.63]). NFV AUC 0-12 was above target in 15 of 18 (83%) of participants during the third trimester compared to 14 of 16 (88%) postpartum. No major safety concerns were noted. Increasing the NFV dose to 1875 mg twice daily during the third trimester achieved similar concentrations postpartum compared to standard dosing (1250 mg twice daily). Increased NFV dose regimens may still have some benefit to human immunodeficiency virus (HIV)-positive pregnant women living in countries where novel protease inhibitors are currently unavailable or in individuals who are intolerant to ritonavir-boosted HIV medications.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Increased Nelfinavir Plasma Concentrations in Women During Pregnancy and Postpartum

Eke

McCormack

Best

et al. 2018

The Journal of Clinical Pharma

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Casette Dosing for Optimization of Toxico(pharmaco)kinetic Investigations

et al. 2016

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Method for predicting the risk of drug–drug interactions involving inhibition of intestinal CYP3A4 and P-glycoprotein

Tachibana¹,

Kato²,

Watanabe

et al. 2009

Xenobiotica

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To develop a method to predict the risk of drug-drug interactions involving the inhibition of intestinal CYP3A4 or P-glycoprotein, data from clinical drug-drug interaction studies of CYP3A4 and/or P-glycoprotein substrates were analysed. The ratio of inhibitor dose (Dose(i)) to inhibition constant (K(i)), termed the drug-interaction number, was used to index intestinal drug-drug interaction. From the analysis, it was found that (1) CYP3A4 inhibitors with a drug-interaction number below 2.8 L have a low risk of interacting with substrates which exhibit intestinal first-pass metabolism and those with a drug-interaction number above 9.4 L have a high risk; (2) P-glycoprotein inhibitors with a drug-interaction number below 10.8 L have a low risk of interacting with P-glycoprotein substrates and those with a drug-interaction number above 27.9 L have a high risk; and (3) the drug-interaction number indexes, 2.8 L and 9.4 L for CYP3A4 and 10.8 L and 27.9 L for P-glycoprotein were validated by data from dual CYP3A4/P-glycoprotein substrates. In conclusion, the drug-interaction number is useful for classifying the risk of drug-drug interactions involving the inhibition of intestinal CYP3A4 and P-glycoprotein. This drug-interaction number-based approach is similar to the method that the US Food and Drug Administration (USFDA) recently proposed in the draft guidance for predicting P-glycoprotein-mediated drug-drug interaction.

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Saquinavir, nelfinavir and M8 pharmacokinetics following combined saquinavir, ritonavir and nelfinavir administration

Abstract: The co-administration of nelfinavir and saquinavir/ritonavir leads to unpredictable changes in concentrations of both drugs. It is unclear whether the increased concentrations of M8 are associated with a clinical benefit.

Cited by 6 publications

References 8 publications

Pharmacokinetics of Increased Nelfinavir Plasma Concentrations in Women During Pregnancy and Postpartum

Pharmacokinetics of Increased Nelfinavir Plasma Concentrations in Women During Pregnancy and Postpartum

Casette Dosing for Optimization of Toxico(pharmaco)kinetic Investigations

Method for predicting the risk of drug–drug interactions involving inhibition of intestinal CYP3A4 and P-glycoprotein

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