Limited Sampling Strategy of Partial Area Under the Concentration–Time Curves to Estimate Midazolam Systemic Clearance for Cytochrome P450 3A Phenotyping

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Drug transporters are present in various tissues and have a significant role in drug absorption, distribution, and elimination. The International Transporter Consortium has identified 7 transporters of increasing importance from evidence of clinically significant transporter-mediated drug-drug interactions. The transporters are P-glycoprotein, breast cancer resistance protein, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter 2, organic anion transporters (OAT) 1, and OAT3. Decision trees were created based on in vitro experiments to determine whether an in vivo transporter-mediated drug-drug interaction study is needed. Phenotyping is a methodology that evaluates real-time in vivo transporter activity, whereby changes in a probe substrate or probe inhibitor reflect alternations in the activity of the specified transporter. In vivo probe substrates and/or probe inhibitors have been proposed for each aforementioned transporter. In vitro findings and animal models provide the strongest evidence regarding probe specificity. However, such findings have not conclusively correlated with human phenotyping studies. Furthermore, the extent of contribution from multiple transporters in probe disposition complicates the ability to discern if study findings are the result of a specific transporter and thus provide a recommendation for a preferred probe for a drug transporter.

Section: Evaluation Of Proposed In Vivo Transporter Probesmentioning

confidence: 99%

“…The limitations of a partial AUC approach are discussed elsewhere. 7,73 The authors also suggested that pitavastatin is a more sensitive and selective OATP1B1 substrate (and therefore probe) compared with rosuvastatin. 26 There is some evidence that pitavastatin may not be a suitable OATP1B1 probe substrate.…”

Section: Oatp1b1 Substratesmentioning

confidence: 99%

Evaluation of Proposed In Vivo Probe Substrates and Inhibitors for Phenotyping Transporter Activity in Humans

Momper

Tsunoda

Joseph

2016

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“…Katzenmaier et al also proposed a partial AUC approach to estimate midazolam metabolic clearance. Conflicting studies exist, and others have suggested that midazolam partial AUC models are unable to accurately estimate midazolam clearance during constitutive and inhibitory CYP3A conditions . Consequently, currently published midazolam limited sampling models have limitations that complicate the ability for general, widespread use.…”

mentioning

confidence: 99%

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

Patel

Nikanjam

et al. 2018

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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 (V ) 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.

“…Because the majority of studies consisted of plasma concentrations, a conversion factor was not used for the single study (n = 13) that used serum concentrations. The data from these studies were used in previous limited sampling analyses involving different independent (eg, partial AUC) and dependent variables (eg, systemic or apparent oral CL) for model development . A single dose of oral (midazolam syrup 2 mg/mL) or intravenous (IV) midazolam of various doses was administered to healthy adults (Table ).…”

Section: Methodsmentioning

confidence: 99%

“…The data from these studies were used in previous limited sampling analyses involving different independent (eg, partial AUC) and dependent variables (eg, systemic or apparent oral CL) for model development. 22,23 A single dose of oral (midazolam syrup 2 mg/mL) or intravenous (IV) midazolam of various doses was administered to healthy adults (Table 1). Intensive midazolam PK profiles were obtained from subjects who received midazolam alone; flumazenil plus midazolam (control phase); and concomitant administration of a known CYP3A inhibitor (ketoconazole or grapefruit juice), CYP3A inducer (rifampin or gingko biloba), or CYP3A activator (pleconaril).…”

Section: Subjectsmentioning

confidence: 99%

Midazolam Limited Sampling Strategy With a Population Pharmacokinetic Approach to Simultaneously Estimate Cytochrome P450 (CYP) 3A Constitutive, Inhibition, and Induction/Activation Conditions in Healthy Adults

Yang

Nikanjam

Capparelli

et al. 2019

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We have previously described a midazolam limited sampling strategy employing a population pharmacokinetic (PK) approach to estimate constitutive cytochrome P450 (CYP) 3A activity. This study evaluated expansion of this approach to estimate CYP3A constitutive, inhibitory, and induction activities. Midazolam concentrations (n = 4441) from adults (n = 152) were obtained from previous studies after single, oral, or intravenous administration with intensive sample collection. Data were fit to a 2‐compartment population PK model that incorporated CYP3A conditions as covariates for clearance (CL), volume of distribution, and bioavailability (F). Limited sampling models using single– or 2–time point concentrations were compared with full PK profiles using the empiric Bayesian post hoc estimations of midazolam area under the plasma concentration–time curve derived from the population PK model. Ketoconazole, rifampin, and pleconaril were significant covariates of CL, while ketoconazole, rifampin, and grapefruit juice were significant covariates for F. Typical midazolam CL and F estimates were 32.9 L/h and 0.31 for the constituent state, while the ratio of inducer/inhibitor for midazolam CL and CL/F for the induced/inhibited (rifampin/ketoconazole) states were 14.2 and 85.3. Upon comparison to the population PK model, the majority of evaluated single– and 2–time point limited sampling models estimated area under the plasma concentration–time curve had unacceptable r2 and/or unacceptable bias and precision. Exclusively during CYP3A inhibitory conditions, the 4‐ and 6‐hour limited sampling model had acceptable limits of r2, bias, and precision. Consequently, development of a single– or 2–time point midazolam limited sampling model for general, widespread use to simultaneously evaluate various CYP3A conditions remains elusive.