Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals

The intestinal efflux transporter breast cancer resistance protein (BCRP) restricts the absorption of rosuvastatin. Of the transporters important to rosuvastatin disposition, fostamatinib inhibited BCRP (IC 50 = 50 nM) and organic anion-transporting polypeptide 1B1 (OATP1B1; IC 50 > 10 mM), but not organic anion transporter 3, in vitro, predicting a drug-drug interaction (DDI) in vivo through inhibition of BCRP only. Consequently, a clinical interaction study between fostamatinib and rosuvastatin was performed (and reported elsewhere). This confirmed the critical role BCRP plays in statin absorption, as inhibition by fostamatinib resulted in a significant 1.96-fold and 1.88-fold increase in rosuvastatin area under the plasma concentration-time curve (AUC) and C max , respectively. An in vitro BCRP inhibition assay, using polarized Caco-2 cells and rosuvastatin as probe substrate, was subsequently validated with literature inhibitors and used to determine BCRP inhibitory potencies (IC 50 ) of the perpetrator drugs eltrombopag, darunavir, lopinavir, clopidogrel, ezetimibe, fenofibrate, and fluconazole. OATP1B1 inhibition was also determined using human embryonic kidney 293-OATP1B1 cells versus estradiol 17b-glucuronide. Calculated parameters of maximum enterocyte concentration [I gut max ], maximum unbound hepatic inlet concentration, transporter fraction excreted value, and determined IC 50 value were incorporated into mechanistic static equations to compute theoretical increases in rosuvastatin AUC due to inhibition of BCRP and/or OATP1B1. Calculated theoretical increases in exposure correctly predicted the clinically observed changes in rosuvastatin exposure and suggested intestinal BCRP inhibition (not OATP1B1) to be the mechanism underlying the DDIs with these drugs. In conclusion, solitary inhibition of the intestinal BCRP transporter can result in clinically significant DDIs with rosuvastatin, causing up to a maximum 2-fold increase in exposure, which may warrant statin dose adjustment in clinical practice.

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“…Value for k a taken to be 0.02 (Arab-Alameddine et al, 2014). d Value taken from Kakuda et al (2011).…”

mentioning

confidence: 99%

Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure

Elsby

Martín

Surry

et al. 2015

Drug Metabolism and Disposition

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“…Missing values for weight, AST and ALT were imputed to the population median value. Darunavir and ritonavir area under the concentration-time curves from zero to 24 h (AUC 24 ) were calculated using previously published population PK models [26]. Non-competitive interaction models including darunavir and ritonavir AUC 24 on CL ator and FR ator-oOH were tested using linear, power or exponential functions.…”

Section: Covariate Modelmentioning

confidence: 99%

Influence of Drug–Drug Interactions on the Pharmacokinetics of Atorvastatin and Its Major Active Metabolite ortho-OH-Atorvastatin in Aging People Living with HIV

et al. 2020

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Background People living with HIV (PLWH) are aging and experience age-related physiological changes and comorbidities. Atorvastatin is a widely prescribed lipid-lowering agent metabolized by cytochrome P450 (CYP) 3A4, whose hepatocyte uptake is facilitated by organic anion transporting polypeptide (OATP) 1B1/1B3. Inhibition or induction of this enzyme and hepatic transporter can increase or decrease atorvastatin exposure, respectively. Objective This study aimed to describe the pharmacokinetic profile of atorvastatin and its major metabolite, and to evaluate drug-drug interactions (DDIs) with antiretrovirals (ARVs). Methods The atorvastatin pharmacokinetic profile was best described by a two-compartment model with first-order absorption and elimination. Metabolite concentrations were described by considering both linear metabolism from atorvastatin and presystemic metabolism. The influence of demographic and clinical covariates on drug and metabolite pharmacokinetics was assessed using NONMEM ®. Model-based simulations were performed to evaluate the magnitude of DDIs with ARVs. Results Full pharmacokinetic profiles (98 atorvastatin + 62 o-OH-atorvastatin concentrations) and sparse concentrations (78 and 53 for atorvastatin and o-OH-atorvastatin, respectively) were collected in 59 PLWH. Interindividual variability was high. The coadministration of boosted ARVs decreased atorvastatin clearance by 58% and slowed down o-OH-atorvastatin formation by 88%. Atorvastatin clearance increased by 78% when coadministered with CYP3A4 inducers. Simulations revealed a 180% increase and 44% decrease in atorvastatin exposure (area under the curve) in the presence of ARVs with inhibiting and inducing properties, respectively. Conclusion This study showed an important interindividual variability in atorvastatin pharmacokinetics that remains largely unexplained after the inclusion of covariates. Since boosted ARVs double atorvastatin exposure, the initial dosage might be reduced by half, and titrated based on individual clinical targets.

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“…Several methods of HIV inactivation, using techniques ranging from solvents or detergents to heat to irradiation, in immunoglobulins, plasma, bone, tissue and blood products have been well documented (Chandra, Groener, & Feldman, ; Miekka et al, ). Although viral inactivation methods specific to quantitative analysis are rare, heat treatment (>56°C) over a period of time (0.5–1 h) appears effective when working with blood and plasma (Aouri et al, ; Arab‐Alameddine et al, ; Barceló et al, ). Most studies involving HIV drugs consider concomitant infections (such as Hepatitis B or C) as exclusion criteria; therefore, only HIV inactivation is required.…”

Section: Literature Review: Bioanalytical Considerationsmentioning

confidence: 99%

Chromatographic methods in HIV medicine: Application to therapeutic drug monitoring

Archibald

Murrell

Brown

2018

Biomedical Chromatography

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HIV antiretroviral therapy spans several different drug classes, meant to combat various aspects of viral infection and replication. Many authors have argued the benefits of therapeutic drug monitoring (TDM) for the HIV patient including compliance assurance and assessment of appropriate drug concentrations; however, the array of drug chemistries and combinations makes TDM an arduous task. HPLC-UV and LC-MS/MS are both frequent instruments for the quantification of HIV drugs in biological matrices with investigators striving to balance sensitivity and affordability. Plasma, the dominant matrix for these analyses, is prepared using protein precipitation, liquidliquid extraction or solid-phase extraction depending on the specific complement of analytes.

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Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals

Abstract: The important variability in darunavir and ritonavir pharmacokinetics is poorly explained by clinical covariates and genetic influences. In experienced patients, treatment simplification strategies guided by drug level measurements and adherence monitoring could be proposed.

Cited by 30 publications

References 25 publications

Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure

Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure

Influence of Drug–Drug Interactions on the Pharmacokinetics of Atorvastatin and Its Major Active Metabolite ortho-OH-Atorvastatin in Aging People Living with HIV

Chromatographic methods in HIV medicine: Application to therapeutic drug monitoring

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