Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens

Tsuchiya, Kiyoto; Gatanaga, Hiroyuki; Tachikawa, Natsuo; Teruya, Katsuji; Kikuchi, Yoshimi; Matsuo, Yoshino; Kuwahara, Taishi; Shirasaka, Takuma; Kimura, Satoshi; Oka, Shinichi

doi:10.1016/j.bbrc.2004.05.116

Cited by 245 publications

(209 citation statements)

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“…In a previous investigation, nevirapine, an inducer of CYP2B6 and CYP3A4, significantly decreased the plasma concentrations of efavirenz, indicating that either CYP2B6 or CYP3A4 or both contribute to the biotransformation of efavirenz [16]. In genetic association studies, the CYP2B6 516 TT genotype was associated with a decreased clearance and increased plasma concentrations of efavirenz in HIV-infected patients [17][18][19], supporting a significant role for CYP2B6 in its biotransformation.…”

Section: Discussionmentioning

confidence: 87%

Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

Forrest

Rosenkranz

et al. 2007

Biopharm & Drug Disp

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The combination of efavirenz with HIV-1 protease inhibitors (PI) results in complex interactions secondary to mixed induction and inhibition of oxidative metabolism. ACTG A5043 was a prospective, open-label, controlled, two-period, multiple-dose study with 55 healthy volunteers. The objective of the present study was to evaluate the potential pharmacokinetic interaction between efavirenz and dual PIs. The subjects received a daily dose of 600 mg efavirenz for 10 days with amprenavir 600 mg twice daily added at day 11 and were randomized to receive nelfinavir, indinavir, ritonavir, saquinavir, or no second PI on days 15-21. Intensive pharmacokinetic studies were conducted on day 14 and 21. Efavirenz plasma concentrations were fit to candidate models using weighted non-linear regression. The disposition of efavirenz was described by a linear two-compartment model with first order absorption following a fitted lag time. Apparent clearance (CL t /F), volume of distribution at steady state (V ss /F), intercompartmental clearance, and the central and peripheral volume of distribution were estimated. The mean CL t /F and V ss /F of efavirenz were 0.126 l/h/kg and 4.412 l/kg, respectively. Both AUC and CL t /F of efavirenz remained unchanged after 7 days of dual PI dosing. The mean V ss /F of efavirenz increased an average of 89% across arms, ranging from 52% (nelfinavir) to 115% (indinavir) relative to efavirenz with amprenavir alone. Increases were also observed in V p /F after the addition of nelfinavir, indinavir, ritonavir and saquinavir by 85%, 170%, 162% and 111%, respectively. In conclusion, concomitant administration of dual PIs is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2B6 substrates in general or oral efavirenz specifically.

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Section: Discussionmentioning

confidence: 87%

Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

Forrest

Rosenkranz

et al. 2007

Biopharm & Drug Disp

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“…For those subjects a lower CYP2B6 mediated clearance of efavirenz and methadone was reported. 47,48 Nevertheless, our investigations clearly show that mephenytoin is not optimal to phenotype for CYP2B6 activity, at least for cross-over studies. First of all, adequate intraindividual variability with coefficients of variation of 23 % resulting in a samples size of 24 subjects were achieved not earlier than 36 hours after cocktail administration.…”

Section: ´-Hydroxymephenytoin Metrics For Cyp2c19 Activitymentioning

confidence: 71%

Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity

Klaassen

Jetter²,

Tomalik-Scharte³

et al. 2007

Eur J Clin Pharmacol

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OBJECTIVES: (S)-Mephenytoin is selectively metabolised to (S)-4'-hydroxymephenytoin by CYP2C19. The urinary excretion of 4'-hydroxymephenytoin reflects the activity of individual enzymes. We evaluated fractioned urinary collection and beta-glucuronidase pre-treatment in order to determine the optimal CYP2C19 metrics. We also assessed whether urinary excretion of N-desmethylmephenytoin (nirvanol) might be a useful CYP2B6 metric in in vivo studies. METHODS: A 50-mg dose of mephenytoin was administered to 52 volunteers as a component of phenotyping cocktails in four separate studies. Urine was collected up to 166 h post-dose. Urinary excretion of 4'-hydroxymephenytoin and nirvanol was quantified by liquid chromatography-tandem mass spectrometry, and common CYP2C19 and CYP2B6 genotypes were determined. RESULTS: Cumulative excretion of 4'-hydroxymephenytoin in urine with beta-glucuronidase treatment collected from before mephenytoin administration up to 12-16 h thereafter showed the greatest difference between CYP2C19 genotypes and the lowest intra-individual variability (7%). Renal elimination of nirvanol was highest for a *4/*4 individual and lowest for individuals carrying the *5/*5 and *1/*7 genotype, but lasted for several weeks, thus making its use in cross-over studies difficult. CONCLUSION: Cumulative urinary excretion of 4'-hydroxymephenytoin 0-12 h post-administration is a sensitive and reproducible metric of CYP2C19 activity, enabling the effect of a drug on CYP2C19 to be assessed in a small sample size of n=6 volunteers. While nirvanol excretion may reflect CYP2B6 activity in vivo, it is not useful for CYP2B6 phenotyping. We evaluated fractioned urinary collection and β-glucuronidase pre-treatment to assess the optimal CYP2C19 metric. Furthermore, we addressed whether urinary excretion of N-desmethylmephenytoin (nirvanol) might be a useful CYP2B6 metric in vivo.Methods: 50 mg of mephenytoin was administered to 52 volunteers as part of phenotyping cocktails in four separate studies. Urine was collected up to 166 hours postdose. Urinary excretion of 4'-hydroxymephenytoin and nirvanol was quantified by LC-MS/MS, and common CYP2C19 and CYP2B6 genotypes were determined.Results: Cumulative excretion of 4'-hydroxymephenytoin in urine with β-glucuronidase treatment collected from before mephenytoin administration up to 12-16 hours thereafter showed the greatest difference between CYP2C19 genotypes and the lowest intraindividual variability (7 %). Renal elimination of nirvanol was highest for a *4/*4 individual and lowest for individuals carrying the *5/*5 and *1/*7 genotype, but lasted for several weeks, thus making its use in cross-over studies difficult. Conclusion:Cumulative urinary excretion of 4'-hydroxymephenytoin 0-12 hours is a sensitive and reproducible metric of CYP2C19 activity, allowing a small sample size of n=6 volunteers to assess the effect of a drug on CYP2C19. While nirvanol excretion may reflect CYP2B6 activity in vivo, it is not useful for CYP2B6 phenotyping.3

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“…Subjects homozygous for the CYP2B6*6 allele, that contains both 516G>T and the 785A>G polymorphisms, display significantly higher EFV plasma levels than heterozygous subjects or those with the common genotype [10]. The 983T>C polymorphism, a less frequent polymorphism only described in Hispanic and black populations, has been shown to impact in EFV exposure as well [11,12].…”

Section: Pharmacogenetics Of Nevirapinementioning

confidence: 99%

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

Barc¹

2013

J Pharmacogenom Pharmacoproteomics

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Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens

Cited by 245 publications

References 9 publications

Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteers

Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

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