Multiple dosing pharmacokinetic models concentrations

The statistical submodel characterizes the pharmacokinetic variability of the mAb and includes the influence of random - that is, not quantifiable or uncontrollable factors. If multiple doses of the antibody are administered, then three hierarchical components of random variability can be defined inter-individual variability inter-occasional variability and residual variability. Inter-individual variability quantifies the unexplained difference of the pharmacokinetic parameters between individuals. If data are available from different administrations to one patient, inter-occasional variability can be estimated as random variation of a pharmacokinetic parameter (for example, CL) between the different administration periods. For mAbs, this was first introduced in sibrotuzumab data analysis. In order to individualize therapy based on concentration measurements, it is a prerequisite that inter-occasional variability (variability within one patient at multiple administrations) is lower than inter-individual variability (variability between patients). Residual variability accounts for model misspecification, errors in documentation of the dosage regimen or blood sampling time points, assay variability, and other sources of error. 

Figure 10.2 Pharmacokinetics of intravenous T-20 administration. The graphs show the expected changes in plasma concentration vs time after intravenous administration of a single injection (dashed line) or multiple injections (solid line) of intravenous T-20 (lOOmg/dose). The curves are based on the half-life (1.8 h) and volume of distribution (4.7 L) measured in 17 human volunteers [4] using a one-compartment model (see Equation 7-3). Because of its rapid elimination, multiple doses are needed to maintain the peptide level in the effective range.

Various pharmacokinetic parameters such as CL, Vd, F%, MRT, and im can be determined using noncompartmental methods. These methods are based on the empirical determination of AUC and AUMC described above. Unlike compartmental models (see below), these calculation methods can be applied to any other models, provided that the drug follows linear pharmacokinetics. However, a limitation of the noncompartmental method is that it cannot be used for the simulation n of different plasma concentration-time profiles when there are alterations in dosing regimen or when multiple dosing regimens are used. 

As previously discussed, compartmental models can be effectively used to project plasma concentrations that would be achieved following different dosage regimen and/or multiple dosing. However, for these projections to be accurate, the drug pharmacokinetic profile should follow first-order kinetics where various pharmacokinetic parameters such as CL, V[Pg.114]

Etoposide causes multiple DNA double-strand breaks by inhibiting topoisomerase II. The pharmacokinetics of etoposide are described by a two-compartment model, with an a half-life of 0.5 to 1 hour and a (5 half-life of 3.4 to 8.3 hours. Approximately 30% of the dose is excreted unchanged by the kidney.16 Etoposide has shown activity in the treatment of several types of lymphoma, testicular and lung cancer, retinoblastoma, and carcinoma of unknown primary. The intravenous preparation has limited stability, so final concentrations should be 0.4 mg/mL. Intravenous administration needs to be slow to prevent hypotension. Oral bioavailability is approximately 50%, so oral dosages are approximate two times those of intravenous doses however, relatively low oral daily dosages are used for 1 to 2 weeks. Side effects include mucositis, myelosuppression, alopecia, phlebitis, hypersensitivity reactions, and secondary leukemias. 

The pharmacokinetics and pharmacodynamics of recombinant interleukin-2 (IL-2) in patients with human immunodeficiency virus (HIV) infection have been evaluated (75). Patients were administered IL-2 either by continuous infusion or by SC injection for 5 days over multiple cycles. Following repeated injection, soluble IL-2 receptors were substantially but transiently increased. A dose-dependent decrease in area under the concentration-time curve (AUC) between days 1 and 5 was attributed to a receptor-mediated change in clearance. Concentrations were described using an unusual model that employed an indirect stimulatory PD model to link the time-dependent changes of the pharmacokinetics with the change in IL-2 receptor density following repeated administration. 

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