Lack of in vivo correlation between indinavir and saquinavir exposure and cytochrome P450 3A phenotype as assessed with oral midazolam as a phenotype probe

Sarah M. Robertson, Elizabeth Formentini, Raul M. Alfaro, Judith Falloon, Scott R. Penzak

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Study Objective. To investigate a potential correlation between exposure to oral midazolam, a commonly used cytochrome P450 (CYP) 3A probe, and saquinavir and indinavir exposure. Design. Open-label, prospective, pharmacokinetic study. Setting. Outpatient research center. Subjects. Thirty-six healthy volunteers aged 22-50 years. Intervention. Subjects received a single oral dose of midazolam 8 mg; 4 hours later, blood was drawn to determine their serum midazolam concentrations. Midazolam phenotyping was followed by successive administration of the protease inhibitors indinavir and saquinavir, with blood sampling and pharmacokinetic analyses performed at steady state. Measurements and Main Results. Pharmacokinetic parameters of each protease inhibitor were evaluated to assess for a potential relationship with 4-hour concentrations of midazolam. No correlations between phenotype results for midazolam and any pharmacokinetic parameter for indinavir or saquinavir were identified (r 2=0.00002-0.073). When the results were analyzed based on race, significant correlations were identified in five African-American subjects, including correlations between 4-hour midazolam levels and apparent oral clearance of saquinavir (r2=0.734, p=0.064), area under the plasma concentration-time curve from 0-8 hours (r2=0.914, p=0.011), minimum concentration (r2=0.857, p=0.024), and maximum concentration (r 2=0.969, p=0.002). These findings for African-American subjects were not seen with indinavir. No correlation was found between indinavir and saquinavir pharmacokinetic parameters (r2=0.017-0.261). Conclusion. Oral midazolam was not a useful probe for predicting saquinavir or indinavir exposure at steady state. Reasons for the lack of correlation likely included differences between midazolam and protease inhibitor P-glycoprotein specificity, differences in the relative contribution of CYP3A5-mediated metabolism, and/or variation in intestinal and hepatic CYP3A specificity. The strong correlation between midazolam phenotype and pharmacokinetic parameters for saquinavir in African-American subjects indicated a racial difference in one or more of these confounding variables.

Original languageEnglish
Pages (from-to)1051-1059
Number of pages9
JournalPharmacotherapy
Volume26
Issue number8 I
DOIs
StatePublished - 1 Aug 2006

Fingerprint

Saquinavir
Indinavir
Cytochrome P-450 CYP3A
Midazolam
Phenotype
Pharmacokinetics
Protease Inhibitors
African Americans
Confounding Factors (Epidemiology)
P-Glycoprotein
Healthy Volunteers
Outpatients
Prospective Studies

Keywords

  • CYP3A phenotype
  • Cytochrome P450 3A phenotype
  • Indinavir
  • Midazolam
  • Pharmacokinetics
  • Protease inhibitors
  • Saquinavir

Cite this

Robertson, Sarah M. ; Formentini, Elizabeth ; Alfaro, Raul M. ; Falloon, Judith ; Penzak, Scott R. / Lack of in vivo correlation between indinavir and saquinavir exposure and cytochrome P450 3A phenotype as assessed with oral midazolam as a phenotype probe. In: Pharmacotherapy. 2006 ; Vol. 26, No. 8 I. pp. 1051-1059.
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abstract = "Study Objective. To investigate a potential correlation between exposure to oral midazolam, a commonly used cytochrome P450 (CYP) 3A probe, and saquinavir and indinavir exposure. Design. Open-label, prospective, pharmacokinetic study. Setting. Outpatient research center. Subjects. Thirty-six healthy volunteers aged 22-50 years. Intervention. Subjects received a single oral dose of midazolam 8 mg; 4 hours later, blood was drawn to determine their serum midazolam concentrations. Midazolam phenotyping was followed by successive administration of the protease inhibitors indinavir and saquinavir, with blood sampling and pharmacokinetic analyses performed at steady state. Measurements and Main Results. Pharmacokinetic parameters of each protease inhibitor were evaluated to assess for a potential relationship with 4-hour concentrations of midazolam. No correlations between phenotype results for midazolam and any pharmacokinetic parameter for indinavir or saquinavir were identified (r 2=0.00002-0.073). When the results were analyzed based on race, significant correlations were identified in five African-American subjects, including correlations between 4-hour midazolam levels and apparent oral clearance of saquinavir (r2=0.734, p=0.064), area under the plasma concentration-time curve from 0-8 hours (r2=0.914, p=0.011), minimum concentration (r2=0.857, p=0.024), and maximum concentration (r 2=0.969, p=0.002). These findings for African-American subjects were not seen with indinavir. No correlation was found between indinavir and saquinavir pharmacokinetic parameters (r2=0.017-0.261). Conclusion. Oral midazolam was not a useful probe for predicting saquinavir or indinavir exposure at steady state. Reasons for the lack of correlation likely included differences between midazolam and protease inhibitor P-glycoprotein specificity, differences in the relative contribution of CYP3A5-mediated metabolism, and/or variation in intestinal and hepatic CYP3A specificity. The strong correlation between midazolam phenotype and pharmacokinetic parameters for saquinavir in African-American subjects indicated a racial difference in one or more of these confounding variables.",
keywords = "CYP3A phenotype, Cytochrome P450 3A phenotype, Indinavir, Midazolam, Pharmacokinetics, Protease inhibitors, Saquinavir",
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Lack of in vivo correlation between indinavir and saquinavir exposure and cytochrome P450 3A phenotype as assessed with oral midazolam as a phenotype probe. / Robertson, Sarah M.; Formentini, Elizabeth; Alfaro, Raul M.; Falloon, Judith; Penzak, Scott R.

In: Pharmacotherapy, Vol. 26, No. 8 I, 01.08.2006, p. 1051-1059.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Lack of in vivo correlation between indinavir and saquinavir exposure and cytochrome P450 3A phenotype as assessed with oral midazolam as a phenotype probe

AU - Robertson, Sarah M.

AU - Formentini, Elizabeth

AU - Alfaro, Raul M.

AU - Falloon, Judith

AU - Penzak, Scott R.

PY - 2006/8/1

Y1 - 2006/8/1

N2 - Study Objective. To investigate a potential correlation between exposure to oral midazolam, a commonly used cytochrome P450 (CYP) 3A probe, and saquinavir and indinavir exposure. Design. Open-label, prospective, pharmacokinetic study. Setting. Outpatient research center. Subjects. Thirty-six healthy volunteers aged 22-50 years. Intervention. Subjects received a single oral dose of midazolam 8 mg; 4 hours later, blood was drawn to determine their serum midazolam concentrations. Midazolam phenotyping was followed by successive administration of the protease inhibitors indinavir and saquinavir, with blood sampling and pharmacokinetic analyses performed at steady state. Measurements and Main Results. Pharmacokinetic parameters of each protease inhibitor were evaluated to assess for a potential relationship with 4-hour concentrations of midazolam. No correlations between phenotype results for midazolam and any pharmacokinetic parameter for indinavir or saquinavir were identified (r 2=0.00002-0.073). When the results were analyzed based on race, significant correlations were identified in five African-American subjects, including correlations between 4-hour midazolam levels and apparent oral clearance of saquinavir (r2=0.734, p=0.064), area under the plasma concentration-time curve from 0-8 hours (r2=0.914, p=0.011), minimum concentration (r2=0.857, p=0.024), and maximum concentration (r 2=0.969, p=0.002). These findings for African-American subjects were not seen with indinavir. No correlation was found between indinavir and saquinavir pharmacokinetic parameters (r2=0.017-0.261). Conclusion. Oral midazolam was not a useful probe for predicting saquinavir or indinavir exposure at steady state. Reasons for the lack of correlation likely included differences between midazolam and protease inhibitor P-glycoprotein specificity, differences in the relative contribution of CYP3A5-mediated metabolism, and/or variation in intestinal and hepatic CYP3A specificity. The strong correlation between midazolam phenotype and pharmacokinetic parameters for saquinavir in African-American subjects indicated a racial difference in one or more of these confounding variables.

AB - Study Objective. To investigate a potential correlation between exposure to oral midazolam, a commonly used cytochrome P450 (CYP) 3A probe, and saquinavir and indinavir exposure. Design. Open-label, prospective, pharmacokinetic study. Setting. Outpatient research center. Subjects. Thirty-six healthy volunteers aged 22-50 years. Intervention. Subjects received a single oral dose of midazolam 8 mg; 4 hours later, blood was drawn to determine their serum midazolam concentrations. Midazolam phenotyping was followed by successive administration of the protease inhibitors indinavir and saquinavir, with blood sampling and pharmacokinetic analyses performed at steady state. Measurements and Main Results. Pharmacokinetic parameters of each protease inhibitor were evaluated to assess for a potential relationship with 4-hour concentrations of midazolam. No correlations between phenotype results for midazolam and any pharmacokinetic parameter for indinavir or saquinavir were identified (r 2=0.00002-0.073). When the results were analyzed based on race, significant correlations were identified in five African-American subjects, including correlations between 4-hour midazolam levels and apparent oral clearance of saquinavir (r2=0.734, p=0.064), area under the plasma concentration-time curve from 0-8 hours (r2=0.914, p=0.011), minimum concentration (r2=0.857, p=0.024), and maximum concentration (r 2=0.969, p=0.002). These findings for African-American subjects were not seen with indinavir. No correlation was found between indinavir and saquinavir pharmacokinetic parameters (r2=0.017-0.261). Conclusion. Oral midazolam was not a useful probe for predicting saquinavir or indinavir exposure at steady state. Reasons for the lack of correlation likely included differences between midazolam and protease inhibitor P-glycoprotein specificity, differences in the relative contribution of CYP3A5-mediated metabolism, and/or variation in intestinal and hepatic CYP3A specificity. The strong correlation between midazolam phenotype and pharmacokinetic parameters for saquinavir in African-American subjects indicated a racial difference in one or more of these confounding variables.

KW - CYP3A phenotype

KW - Cytochrome P450 3A phenotype

KW - Indinavir

KW - Midazolam

KW - Pharmacokinetics

KW - Protease inhibitors

KW - Saquinavir

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U2 - 10.1592/phco.26.8.1051

DO - 10.1592/phco.26.8.1051

M3 - Article

C2 - 16863481

AN - SCOPUS:33746756632

VL - 26

SP - 1051

EP - 1059

JO - Pharmacotherapy

JF - Pharmacotherapy

SN - 0277-0008

IS - 8 I

ER -