Population one-compartment pharmacokinetic analysis with missing dosage data.

Dolors Soy; Stuart L Beal; Lewis B Sheiner

doi:10.1016/j.clpt.2004.07.010

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Population one-compartment pharmacokinetic analysis with missing dosage data.

Dolors Soy·Stuart L Beal·Lewis B Sheiner

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Abstract

OBJECTIVE: Our objective was to develop a population 1-compartment pharmacokinetic (PK) method of analysis to deal with suspect or missing prior dosage history. METHODS: Population PK data from a 1-compartment model with first-order elimination and absorption, described by PK parameters clearance, volume of distribution, and absorption rate constant, are simulated. A PK sample is drawn just before a test dose (Dt), followed by a (varying) number of additional samples over 1 interdose interval (tau). For 60% of the subjects, the true history of the scheduled dose (Ds) preceding Dt differs from that prescribed, whereas doses taken before Ds do not. Two settings are evaluated: considerable accumulation of drug in the body (typical drug half-life t1/2 approximately equal to tau) and very little such accumulation (t1/2 approximately equal to tau/5). Precision and bias of several PK analysis methods--Missing Dose Method (MDM), Missing Dose Mixture Method (MDMM) and Extrapolation-Subtraction Method (ESM), all of which essentially do not use prior dose history--are compared with those of the Prescribed Dose Method (PDM), which assumes nominal dosage, and an Ideal Method (IDM), which uses true (but unknown) pre-test dose history. RESULTS: At t1/2 approximately equal to tau, MDM and MDMM are the most precise methods. The accuracy of ESM and PDM is poor. At t1/2 approximately equal to tau/5, no significant differences, in terms of precision or bias, are observed between methods. Misspecification of the structural or statistical model seems not to influence these results. The results of analysis of a real (caffeine) data set are compatible with the findings from the simulations. CONCLUSION: When a test dose is given and a predose baseline observation is taken as part of an "intensive" PK study during outpatient therapy of a 1-compartment drug, an analysis that assumes that the nominal dose history is correct is not robust to past dosage history misspecification, whereas methods that do not do this are robust and reliable.

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Absorption Algorithms Computer Simulation Dose-Response Relationship, Drug Drug Prescriptions Half-Life Humans Models, Statistical Pharmacokinetics Population Reproducibility of Results Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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Dolors Soy, Stuart L Beal, Lewis B Sheiner. 2004. Population one-compartment pharmacokinetic analysis with missing dosage data.. https://doi.org/10.1016/j.clpt.2004.07.010

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