Pharmacokinetic and Pharmacodynamic Modeling of Pegylated Thrombopoietin Mimetic Peptide (PEG‐TPOm) After Single Intravenous Dose Administration in Healthy Subjects

Abstract

Pegylated thrombopoietin mimetic peptide (PEG-TPOm) is a novel, potent thrombopoietin receptor agonist with low immunotoxicity potential that protects against chemotherapy-induced thrombocytopenia in preclinical animal models. The aim of this study was to develop a population pharmacokinetic and pharmacodynamic model of PEG-TPOm following single intravenous doses in healthy subjects. Data were obtained from a double-blind, randomized, placebo-controlled study. A model based on target-mediated drug disposition and precursor pool life spans was applied. Model evaluation was performed through predictive checks and bootstrap analysis. The half-life of PEG-TPOm ranged between 18 and 36 hours, and the estimated distributional volume was 5 L. The increase in platelet counts was observed after a 4-day delay, consistent with the megakaryocyte cell life span. The platelet life span was estimated to be 5 days. After maximum platelets counts were achieved on day 9, platelets returned back to baseline on day 29. Model-based simulations were undertaken to explore pharmacodynamic effects after multiple dosing. Weekly dosing produced a sustained pharmacodynamic response, whereas an interdosing interval >or=2 weeks resulted in fluctuating pharmacodynamic profiles. Thus, the mechanistic pharmacokinetic/pharmacodynamic model was suitable for describing the complex PEG-TPOm pharmacokinetics/pharmacodynamics, including target-mediated disposition, dose-dependent platelet stimulation, and mean life spans of thrombopoietic cell populations.

Pharmacodynamics-Mediated Drug Disposition (PDMDD) and Precursor Pool Lifespan Model for Single Dose of Romiplostim in Healthy Subjects

“…We estimated a 28% receptor occupancy is needed to achieved 50% of the maximal stimulatory effect (Fig. 8), which is similar to the value previously reported by Samtani et al (20). These results confirm the high potency of romiplostim and explain why platelet responses were similar after IV and SC administration receiving the same dose level, despite the large differences in the exposures.…”

“…These results support the spare receptor theory (23) as an explanation to the romiplostim mechanism of action. This pharmacological theory has been previously reported for other TRAs (20,23,24).…”

“…All blood samples were centrifuged, and separated serum was stored at −70°C until the analysis was conducted. Platelet counts were determined from blood samples collected as part of a complete blood cell count at screening, before dosing, and on study days 2, 3,5,8,10,11,12,13,14,15,17,20,28, and 42 using a hematology analyzer.…”

Model Evaluation of Continuous Data Pharmacometric Models: Metrics and Graphics

“…suggested that parameter uncertainty could be ignored in data simulation if it is negligible with respect to the between and within subject variability and the sample size available. Otherwise, the computation of simulation‐based metrics should account for uncertainty in the model parameter 35. Even though simulation‐based evaluation tools now have become standard evaluation graphs, which are reported in most population analysis, they may still remain less familiar than classical evaluation tools, such as predictions or weighted residuals to audiences composed of nonmodelers.…”

Genetic Pharmacotherapy

“…This causes the dose-response curve to shift to the left of the receptor occupancy curve, so that a drug dose that elicits maximal tissue response may cause only partial occupation of the available receptors ( Figure 5). For example, opiate agonists etorphine and sufentanil have significant analgesic activity at very low receptor occupancy -approximately 2% at the ED 50 (Rosenbaum et al, 1984); and in another example, only 22% receptor occupancy is needed for half-maximal stimulation by PEG-TPOm, a mimetic peptide agonist in development for protection against chemotherapy-induced thrombocytopenia (loss of blood platelets) (Samtani et al, 2009). The antipsychotic dopamine D2 receptor antagonist olanzapine achieves optimal clinical efficacy at about 60% receptor occupancy (Mamo et al, 2007).…”