1A Bayesian Approach for Population Pharmacokinetic Modeling of Dihyroartemisinin Bayesian Statistics (22S:138) – Project Final Report Beesan Tan, Thitima Wattanavijitkul, Lanyi Xie December 10, 2007 ABSTRACT Dihydroartemisinin (DHA) is an active metabolite of artesunate (ARTS) and is highly effective in the treatment of malaria, a life threatening parasitic disease. ARTS causes rapid reduction in parasitemia and fever in patients with falciparum malaria and is associated with a radical cure rate of (> 90%) if administered for a period of 5-7 days. A phase I single oral dose escalation study in healthy volunteers was conducted to characterize the pharmacokinetics and to assess safety and tolerability of ARTS and DHA. The study was a randomized, double-blind placebo-controlled, staggered, parallel design to study ARTS doses from 2 to 5 mg/kg in 36 healthy Korean subjects. Plasma samples for pharmacokinetic assessment were obtained at regular time intervals and analyzed using a previously validated LC-MS method. Non-compartmental method of analysis was used for the determination of pharmacokinetic parameters using WinNonlin. Since ARTS is rapidly and almost completely converted to its active metabolite DHA, in this present study we are interested only in characterizing the pharmacokinetics of DHA by a Bayesian approach with PKBugs/WinBUGS using data from this completed phase I trial. Permission to use the dataset was obtained from Dr. L. Fleckenstein, the director of the Clinical Pharmacokinetics Lab, College of Pharmacy. In conclusion, using a Bayesian approach with a one-compartment structural model with first order input and elimination, the estimates for Cl/F, V/F, tlag, ke and ka for DHA were 130.06 L/hr, 195.98 L, 8.34 minutes, 0.664/hr and 1.271/hr respectively.2INTRODUCTION Malaria Malaria is among the top 10 killer diseases in the world. It accounts for1.5 to 2.7 million deaths worldwide, 90% of which occur in tropical Sahara, where malaria is the leading cause of mortality in children under five years of age. Outside Africa, some two-thirds of the remaining cases occur in just three countries; Brazil, India and Sri Lanka. However, malaria exists in some 100 countries, which are visited by more than 125 million international travelers every year1. In 2005, it is reported that over 10,000 international travelers were infected with malaria while visiting countries where the disease is endemic. Due to under-reporting, the exact figure may be as high as 30,0002. Therefore, malaria is not a problem confined to African countries anymore, but a real world health issue. Malaria is a life threatening parasitic disease transmitted by anopheles mosquitoes. Human malaria is caused by four different species of the protozoan parasite Plasmodium: Plasmodium falciparum, P. vivax, P. ovale and P. malariae. The most severe form of the disease is caused by P. falciparum, in which variable clinical features include fever, chills, headache, muscular aching and weakness, vomiting, cough, diarrhea and abdominal pain; other symptoms related to organ failure may supervene, such as: acute renal failure, generalized convulsions, circulatory collapse, followed by coma and death3. The main factor contributing to the increasing malaria mortality and morbidity is the widespread resistance of P. falciparum to conventional antimalarial drugs, such as chloroquine, sulfadoxine–pyrimethamine (SP) and amodiaquine. Therefore, WHO recommends the use of combination therapies, preferably those containing artemisinin derivatives, in countries experiencing resistance to conventional monotherapies4. Artesunate-pyronaridine combination is one of the antimalarial drugs under development to combat the issue of resistance. Artemisinin, artesunate and dihydroartemisinin Artemisinin (Qinghaosu) is a naturally occurring sesquiterpene lactone containing an endoperoxide group extracted from the leaves of Chinese herb Artemisia annua. Studies in China, Vietnam and Thailand have shown that artemisinin and its derivatives quickly reduce parasitemia in patient with acute falciparum malaria and induce fast resolution of symptoms without any toxicity5,6. Parasitic and fever clearance times have been shown to be shorter than those observed with other classical antimalarials. Various derivatives of artemisinin with improved pharmacological properties have been synthesized because artemisinin is poorly soluble in either water or oil. These include sparingly water soluble artesunate (ARTS) and the lipophilic alkyl ethers: arteether and artemether. Artesunate (ARTS) is a water-soluble hemisuccinate ester of dihydroartemisinin (DHA) and is highly effective in the treatment of malaria. ARTS is one of the semi synthetic derivative of artemisinin developed for clinical use, and has advantage over the naturally occurring product in that it can be administered parenterally, an important factor for use in patient with severe falciparum malaria. ARTS is rapidly converted to its active metabolite DHA in vivo which is responsible for the antimalarial action. Hence, it is regarded3as a prodrug of DHA. Substantial conversion into DHA takes place in the intestine and liver prior to reaching the systemic circulation. Pharmacokinetic concepts Pharmacokinetics (PK), sometimes referred to as what the body does to a drug, is the study of the time course of the drug concentrations within a biological system. Concentrations over time are determined by the rate and extent of the processes of absorption, distribution, metabolism, and excretion (ADME). Pharmacokinetics is often studied in conjunction with pharmacodynamics which describe as what a drug does to the body. A standard approach to describing PK behavior is to represent the body by a series of compartments. Under a specified route of administration of drug, the compartmental representation leads to a system of differential equations in terms of parameters related to the ADME processes to describe mathematically the instantaneous rates of change of the amounts or concentrations of agent residing in each compartment based on assumptions on how the drug moves within and among the compartments. The solution of the system provides a formal mathematical description of the concentrations in the compartments at any time as a function of the parameters. The concentrations of the drug in blood over time are dictated by some pharmacokinetic parameters, such as clearance,
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