A model based assessment of the CYP2B6 and CYP2C19 inductive properties by artemisinin antimalarials: implications for combination regimens

Elsherbiny, Doaa A.; Asimus, Sara; Karlsson, Mats O.; Ashton, Michael; Simonsson, Ulrika S. H.

doi:10.1007/s10928-008-9084-6

Cited by 33 publications

(24 citation statements)

References 20 publications

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“…Auto-induction of CYP2B6 and CYP2C19 was proposed to be the main mechanism causing the decline of plasma ARN concentrations [36-38]. A semi-physiological pharmacokinetic model taking into account the autoinduction phenomenon has been developed for ARN in healthy subjects [39].…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects

Tan

Naik

Jang

et al. 2009

Malar J

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BackgroundThe population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food.MethodsData from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability) parameter estimates.ResultsA novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka) of 3.85 h-1. The population estimates of apparent clearance (CL/F) and volume of distribution (V2/F) for AS were 1190 L/h with 36.2% inter-individual variability (IIV) and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F) and central volume of distribution (V3/F) were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F) and peripheral volume of distribution (V4/F) for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in weight resulted in 1.9-unit change in CLM/F in the same direction.ConclusionsA novel simultaneous parent-metabolite pharmacokinetic model with good predictive power was developed to study the population pharmacokinetics of AS and DHA in healthy subjects following single- and multiple-dosing of AS with or without the presence of food. Food intake and weight were significant covariates for Ka and CLM/F, respectively.

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects

Tan

Naik

Jang

et al. 2009

Malar J

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“…Therefore, the autoinduction observed with QHS drugs may be a result of autoinduction of CYP3A and/or CYP2B6. This has been shown for CYP2B6 in vivo (Simonsson et al, 2003;Elsherbiny et al, 2008). Induction of CYP3A4 and CYP2B6 mRNA expression by QHS has been observed in primary human hepatocytes and in the human intestinal cell line LS174T (Burk et al, 2005), and activation of CYP3A4 by QHS drugs was found in healthy subjects (Asimus et al, 2007).…”

Section: Discussionmentioning

confidence: 66%

Evaluation of P450 Inhibition and Induction by Artemisinin Antimalarials in Human Liver Microsomes and Primary Human Hepatocytes

et al. 2012

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ABSTRACT:Artemisinin drugs have become the first-line antimalarials in areas of multidrug resistance. However, monotherapy with artemisinin drugs results in comparatively high recrudescence rates. Autoinduction of cytochrome P450 (P450)-mediated metabolism, resulting in reduced exposure, has been supposed to be the underlying mechanism. To better understand the autoinduction and metabolic drug-drug interactions (DDIs), we evaluated the P450s (particularly CYP2B6 and CYP3A4) inhibited or induced by two artemisinin drugs, Qing-hao-su (QHS) and dihydroartemisinin (DHA) using human liver microsome, recombinant P450 enzymes, and primary human hepatocytes. The results suggested that QHS was a weak reversible inhibitor of CYP2B6 (K i 4.6 M), but not CYP3A4 (IC 50 ϳ 50 M) and did not show measurable time-dependent inhibition of either CYP2B6 or CYP3A4. DHA inhibited neither CYP2B6 nor CYP3A4 (IC 50 > 125 M). In addition, it was found that QHS induced the activity of CYP3A4 (E max 3.5-fold and EC 50 5.9 M) and CYP2B6 (E max 1.9-fold and EC 50 0.6 M). Of the other P450s, UDP glucuronosyltransferases, and transporters studied, QHS and DHA had no significant effect except for minor induction of mRNA expression of CYP1A2 (E max 7.9-fold and EC 50 5.2 M) and CYP2A6 (E max 11.7-fold and EC 50 4.0 M) by QHS. Quantitative prediction of P450-mediated DDIs indicate autoinduction of QHS clearance with the AUC i /AUC ratio decreasing to 59%, as a result of a 1.9-fold increase in CYP3A4 and a 1.6-fold increase in CYP2B6 activity. These data suggest that QHS drugs are potential inducers of P450 enzymes, and the possible drug interactions (or lack thereof) with artemisinin drugs may be clinically relevant.

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“…Artemisinin ü ü CYP2A6 Nicotine, coumarin [165] CYP2B6 Mephenytoin [166,167] CYP2C19 Omeprazole, mephenytoin [167,168] Bosentan ü CYP2C9 S-Warfarin [169] CYP3A4 Cyclosporine, glibenclamide, simvastatin [169] Carbamazepine ü ü CYP1A2 Caffeine [170] CYP2C9 Warfarin [171] CYP2B6 Bupropion [172] CYP3A4 Midazolam, alprazolam [173,174] Dexamethasone ü CYP3A4 Erythromycin [175] Efavirenz ü ü CYP3A4 Midazolam, atorvastatin [176] Indole-3-carbinol ü CYP1A2 Caffeine [177,178] Omeprazole ü CYP1A2 Caffeine [179,180] PAHs* ü CYP1A1 qPCR z [181] CYP1B1 qPCR z [182] Phenobarbital § ü ü CYP1A2 Theophylline [183] CYP2B6 Cyclophosphamide [184] CYP2C19 Hexobarbital [185] CYP3A4 Ethynylestradiol [186] Phenytoin ü ü CYP1A2 Theophylline [187] CYP2B6 Cyclophosphamide [188] CYP3A4 Lopinavir, midazolam [173,189] Rifampicin ü CYP1A2 Tizanidine, caffeine [190] CYP2B6 Bupropion [191] CYP2C8 Repaglinide, pioglitazone, rosiglitazone [192][193][194] CYP2C9 Warfarin, tolbutamide, glipizide [195,196] CYP2C19 Omeprazole [197] CYP3A4 Midazolam, nifedipine, repaglinide, zolpidem [6,[198][199][200] Ritonavir (with lopinavir) ü CYP1A2 Caffeine [201] CYP2B6 Buprop...…”

Section: Pxr Car Ahrmentioning

confidence: 99%

Methods for the quantitative evaluation and prediction of CYP enzyme induction using humanin vitrosystems

Honma

Kozawa

Suzuki

2010

Expert Opinion on Drug Discovery

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A model based assessment of the CYP2B6 and CYP2C19 inductive properties by artemisinin antimalarials: implications for combination regimens

Cited by 33 publications

References 20 publications

Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects

Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects

Evaluation of P450 Inhibition and Induction by Artemisinin Antimalarials in Human Liver Microsomes and Primary Human Hepatocytes

Methods for the quantitative evaluation and prediction of CYP enzyme induction using humanin vitrosystems

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