Data Analysis

The analysis of the study will depend on the study design characteristics. Total and unbound plasma drug/metabolite concentrations (and urinary excretion data, if collected) can be used to estimate PK parameter. The PK parameters can include the area under the plasma concentration curve (AUC), peak concentration (Cmax), plasma clearance (CLT) or the apparent oral clearance (CL/F), apparent volume of distribution (Vz/F or VSS/F), and terminal half-life (t1/2). Pharmacokinetic parameters should be expressed in terms of total and unbound concentrations. For drugs and metabolites with a relatively low extent of plasma protein binding (e.g., extent of binding less than 80%), description and analysis of PK in terms of total concentrations are usually sufficient. Noncompartmental- and/or compartmental-modeling approaches to parameter estimation can be employed.

Mathematical models for the relationship between pregnancy status and relevant PK parameters can be constructed. The categorization of gestational age, either as a nominal (e.g., trimester) or a continuous (week of gestation) variable will direct the appropriate type of analysis. The analysis may provide an estimation of PK/PD parameters, modeling of the PK/PD relationship, and modeling of the relationship between gestational age and the PK parameters. The models selected should be adequately supported by the data and/or mechanistic arguments.

In addition, an assessment of whether dosage adjustment is warranted in pregnant patients and recommendations for dosing can be further extrapolated. Typically the dose is adjusted to produce a comparable range of unbound plasma concentrations of drug or active metabolites at baseline (prepregnancy or postpartum) compared to that during pregnancy. Simulations may identify doses and dosing intervals that achieve the goal for pregnant patients at different trimesters or gestational ages. Special statistical considerations may be necessary for longitudinal study designs given the repeated measures characteristics of the design.

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