Midazolam Single Time Point Concentrations to Estimate Exposure and Cytochrome P450 (CYP) 3A Constitutive Activity Utilizing Limited Sampling Strategy With a Population Pharmacokinetic Approach

Jincheng Yang, Maulik Patel, Mina Nikanjam, Edmund V. Capparelli, Shirley M. Tsunoda, Howard E. Greenberg, Scott Robert Penzak, S. Aubrey Stoch, Joseph S. Bertino, Anne N. Nafziger, Joseph D. Ma

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2 Citations (Scopus)

Abstract

Midazolam is the preferred probe to phenotype cytochrome P450 (CYP) 3A activity. This study evaluated a single-concentration, midazolam limited sampling strategy utilizing a population pharmacokinetic (PK) approach to estimate area under the curve, and thus CYP3A activity. Midazolam concentrations from adults during CYP3A constitutive conditions were obtained from previous studies after single, oral or intravenous administration. Population PK modeling was conducted by nonlinear mixed-effects modeling. Potential covariates of clearance, volume of distribution, and bioavailability were evaluated. A limited sampling model at 1, 2, 4, or 6 hours was selected and fitted with post hoc estimation with the final population PK model. Preset criterion for the limited sampling model selection was a coefficient of determination ≥0.9. Bias and precision were also evaluated. The studies provided 2122 observations from 152 healthy adults. Midazolam concentrations were adequately described by a two-compartment model with first order absorption. Age and sex were significant covariates of central volume (V2) and were retained in the final model. An estimate (interindividual variability) of midazolam clearance was 32.5 L/hr (52.9%), covariate of central volume was 67 L (39.1%), and oral bioavailability was 0.33 (45.5%). The final population parameter estimates were within the 95% confidence intervals and were similar to the median bootstrap estimates. Upon comparison to the population PK model, the 4-hour limited sampling model estimated area under the curve had an acceptable coefficient of determination and acceptable bias and precision limits. A 4-hour, but not the 1-, 2-, and 6-hour, single concentration accurately estimated midazolam area under the curve during constitutive CYP3A conditions in healthy adults.

Original languageEnglish
Pages (from-to)1205-1213
Number of pages9
JournalJournal of Clinical Pharmacology
Volume58
Issue number9
DOIs
StatePublished - 1 Sep 2018

Fingerprint

Cytochrome P-450 CYP3A
Midazolam
Pharmacokinetics
Population
Area Under Curve
Biological Availability
Intravenous Administration
Oral Administration
Confidence Intervals
Phenotype

Keywords

  • cytochrome P450 3A
  • drug-drug interaction
  • midazolam
  • phenotyping

Cite this

Yang, Jincheng ; Patel, Maulik ; Nikanjam, Mina ; Capparelli, Edmund V. ; Tsunoda, Shirley M. ; Greenberg, Howard E. ; Penzak, Scott Robert ; Aubrey Stoch, S. ; Bertino, Joseph S. ; Nafziger, Anne N. ; Ma, Joseph D. / Midazolam Single Time Point Concentrations to Estimate Exposure and Cytochrome P450 (CYP) 3A Constitutive Activity Utilizing Limited Sampling Strategy With a Population Pharmacokinetic Approach. In: Journal of Clinical Pharmacology. 2018 ; Vol. 58, No. 9. pp. 1205-1213.
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abstract = "Midazolam is the preferred probe to phenotype cytochrome P450 (CYP) 3A activity. This study evaluated a single-concentration, midazolam limited sampling strategy utilizing a population pharmacokinetic (PK) approach to estimate area under the curve, and thus CYP3A activity. Midazolam concentrations from adults during CYP3A constitutive conditions were obtained from previous studies after single, oral or intravenous administration. Population PK modeling was conducted by nonlinear mixed-effects modeling. Potential covariates of clearance, volume of distribution, and bioavailability were evaluated. A limited sampling model at 1, 2, 4, or 6 hours was selected and fitted with post hoc estimation with the final population PK model. Preset criterion for the limited sampling model selection was a coefficient of determination ≥0.9. Bias and precision were also evaluated. The studies provided 2122 observations from 152 healthy adults. Midazolam concentrations were adequately described by a two-compartment model with first order absorption. Age and sex were significant covariates of central volume (V2) and were retained in the final model. An estimate (interindividual variability) of midazolam clearance was 32.5 L/hr (52.9{\%}), covariate of central volume was 67 L (39.1{\%}), and oral bioavailability was 0.33 (45.5{\%}). The final population parameter estimates were within the 95{\%} confidence intervals and were similar to the median bootstrap estimates. Upon comparison to the population PK model, the 4-hour limited sampling model estimated area under the curve had an acceptable coefficient of determination and acceptable bias and precision limits. A 4-hour, but not the 1-, 2-, and 6-hour, single concentration accurately estimated midazolam area under the curve during constitutive CYP3A conditions in healthy adults.",
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author = "Jincheng Yang and Maulik Patel and Mina Nikanjam and Capparelli, {Edmund V.} and Tsunoda, {Shirley M.} and Greenberg, {Howard E.} and Penzak, {Scott Robert} and {Aubrey Stoch}, S. and Bertino, {Joseph S.} and Nafziger, {Anne N.} and Ma, {Joseph D.}",
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Yang, J, Patel, M, Nikanjam, M, Capparelli, EV, Tsunoda, SM, Greenberg, HE, Penzak, SR, Aubrey Stoch, S, Bertino, JS, Nafziger, AN & Ma, JD 2018, 'Midazolam Single Time Point Concentrations to Estimate Exposure and Cytochrome P450 (CYP) 3A Constitutive Activity Utilizing Limited Sampling Strategy With a Population Pharmacokinetic Approach', Journal of Clinical Pharmacology, vol. 58, no. 9, pp. 1205-1213. https://doi.org/10.1002/jcph.1125

Midazolam Single Time Point Concentrations to Estimate Exposure and Cytochrome P450 (CYP) 3A Constitutive Activity Utilizing Limited Sampling Strategy With a Population Pharmacokinetic Approach. / Yang, Jincheng; Patel, Maulik; Nikanjam, Mina; Capparelli, Edmund V.; Tsunoda, Shirley M.; Greenberg, Howard E.; Penzak, Scott Robert; Aubrey Stoch, S.; Bertino, Joseph S.; Nafziger, Anne N.; Ma, Joseph D.

In: Journal of Clinical Pharmacology, Vol. 58, No. 9, 01.09.2018, p. 1205-1213.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Midazolam Single Time Point Concentrations to Estimate Exposure and Cytochrome P450 (CYP) 3A Constitutive Activity Utilizing Limited Sampling Strategy With a Population Pharmacokinetic Approach

AU - Yang, Jincheng

AU - Patel, Maulik

AU - Nikanjam, Mina

AU - Capparelli, Edmund V.

AU - Tsunoda, Shirley M.

AU - Greenberg, Howard E.

AU - Penzak, Scott Robert

AU - Aubrey Stoch, S.

AU - Bertino, Joseph S.

AU - Nafziger, Anne N.

AU - Ma, Joseph D.

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KW - drug-drug interaction

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KW - phenotyping

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