Design of Drug Dosage Regimen (DDR) for Immune Thrombocytopenic Purpura (ITP) Patients Using Control Theory Concepts: A Simulation Study

Introduction

Drug delivery is the process of administering pharmaceuticals to the human body, including the drug's consequent effects on tissues and organs. Mathematical modeling of drug delivery can be divided into two different complementary approaches, the pharmacokinetic approach and the pharmacodynamic approach. Pharmacokinetics describes the effect of a drug in the body by recording drug absorption, distribution, diffusion, and excretion. Pharmacodynamics describes the effects of drugs in the body and is expressed mathematically through drug dose-body-response relationships. Usually, modeling of the drug delivery system requires a pharmacokinetic part, a pharmacodynamics part, and a link between the two. This PK/PD model is utilized for both pre-approval of a drug for clinical trial study and post-approval of the drug for dosage regimen design for specific inline with standard clinical guidelines as shown in Figure 1.

Figure 1.

Block diagram of patient PK/PD model and its application

Chronic immune thrombocytopenia (Chronic ITP) is a condition of low levels of platelets in human blood. Platelets are those cells that help in clotting and control bleeding (Gilbert et al., 2020). The platelet count for a healthy individual is between 150,000 to 400,000 (150 to 400 x 10^9/L) number of platelets per microliter (mcL). The platelet counts (PLT) less than 150x10⁹/L is considered as an IITP patient. But the PLT less than 30x10⁹/L is treated as severe ITP with a high risk of bleeding. A complete blood count (CBC) test measures the number of platelets in human blood.

Romiplostim is a suggested prescription medicine to treat patients with low blood platelet counts (thrombocytopenia) in adults with immune thrombocytopenia when the patients have an insufficient response to other treatments like corticosteroids, immunoglobulins, or splenectomy. The romiplostim injection helps prevent excessive blood loss, stops bleeding, and enhances the healing process (Bidika et al., 2020; Bussel et al., 2021; Christakopoulos et al., 2021; Selleslag et al., 2014). Kuter et al. (2013, 2020) presents the effects of romiplostim infusion and the significant improvements it brings in the quality of life with the lower bleeding event. It is not suggested for people with a precancerous condition called myelodysplastic syndrome (MDS) or low platelet count caused by any condition other than immune thrombocytopenia (ITP) (Keating, 2012).

In the current practice, the Romiplostim is administered as a weekly once subcutaneous injection with dose adjustments based upon the platelet count response (El-beblawy et al., 2015). The first dose of romiplostim is based on actual body weight. The weekly dose is adjusted in increments of until the platelet count is 50 × 10⁹/L or higher. When the platelet count exceeds 200 × 10⁹/L for two consecutive weeks, the dose should be reduced by weekly. When the platelet counts exceed 400 × 10⁹/L, the dose is withheld until the count has fallen below 200 × 10⁹/L. The dose can then be resumed with a reduction of weekly. The maximum weekly dose is . But this dosage regimen does not ensure an optimal drug delivery policy in order to achieve and maintain a platelet count of or greater to reduce bleeding risk.