Woo Yul Lee[1,2], Dongwoo Chae[1], Choon Ok Kim[3]* and Kyungsoo Park[1]*
[1]Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea. [2]Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Korea. [3]Department of Clinical Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
Background: Malaria is the main burden to mankind; worldwide, about 3.2 billion people are at risk of infection and about 228 million people are infected per year, causing about 405,000 deaths in the year of 2018 [1]. A daily dose of 15mg of primaquine (PQ) in combination with other anti-parasitic drugs has long been used as a treatment of choice for malaria caused by Plasmodium Vivax infection [2,3]. Despite clinical experiences with PQ so far, there have been questions about the adequacy of the currently recommended dose regimen, since the relapse of disease or treatment failure is not rare, especially in the obese population [4,5]. Besides, no study has been done in this area in the Asian population. In this regard, it was intended to investigate pharmacokinetic (PK) characteristics of malaria in Korean population in the context of a population approach to find out factors associated with variability of individual PK and accuracy of dose regimen design
Objectives: The aim of this study is to develop a population pharmacokinetic model of primaquine and its metabolite, carboxyprimaquine (CPQ), and examine factors influencing PK variability in the Korean population
Methods: An open-label, parallel designed clinical study was conducted at Severance Hospital Clinical Trial Center. Subjects were randomly assigned to two groups of normal body weight and obese groups according to their BMI. The normal body weight group included subjects with BMI ranging between 18.5–24.9 kg/m2, and the obese group included subjects with BMI ≥ 25.0 kg/m2. A total of 24 healthy volunteers were enrolled in this study, with 12 subjects allocated to each group. Following the radical cure regimen of P.vivax malaria currently used, all participants received a daily dose of 15mg of PQ for 4 days along with a total dose of 2000mg of hydroxy-chloroquine (800 and 400mg given at 0 and 10h of Day 1, respectively, and 400mg given at 0h of Day 2 and 3, respectively, with 0h denoting dosing time of PQ each day). Blood samples were collected at 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24h at D4 for PK analysis. Plasma PQ and CPQ concentrations were fitted simultaneously using mammillary compartment models. With the final model, AUCtau (Area Under the Curve in dose interval) and Cmax (maximum concentration) of PQ and CPQ were simulated for conventional-dose and alternative doses of 0.25mg/kg within different body weight (60kg, 70kg, 80kg, 90kg, 100kg) to compare their exposures. For the genetic influence, the CYP2D6 activity score (AS) was analyzed according to its phenotype.
Results: A semi-mechanistic model with one distribution compartment and a liver compartment successfully estimated the two main clearance pathways of PQ, CYP450 (mainly CYP2D6) and monoamine oxidase (MAO) pathways. Body-weight was incorporated via allometry into clearance and volume parameters of PQ and CPQ with its exponent fixed to 0.75 and 1, respectively. The estimated clearance via CYP2D6 (CLCYP) and MAO were 5.7 (L/h) and 19.2 (L/h), respectively. The volume of distribution of PQ and CPQ was 133.6 L and 29.9 L respectively. The model predicted mean AUCtau in the normal-weight group and the obese group given 15mg of PQ was 630 (ng⸱h/mL) and 547 (ng⸱h/mL), respectively. The simulated AUCtau for the virtual group with 60kg and 100kg bodyweight given 15mg of PQ for 14 days was 666 (ng⸱h/mL) and 455 (ng⸱h/mL) respectively. The simulated AUCtau of PQ and CPQ with an adjusted dose of 0.25mg/kg PQ within different bodyweight yielded similar AUCtau levels. Exponentially affected by CYP2D6 AS, CLCYP was modeled as being multiplied by EXP(1.27*(AS-1.5)).
Conclusion: The exposure of PQ showed a significant relationship with body weight. The AUC of PQ decreased as the bodyweight increased. We suggest that dose should be adjusted to 0.25 mg/kg, to ensure therapeutic exposure in treating malaria and in preventing the relapse of disease, especially in a patient with a heavyweight.
References:
[1] (Bahk et al., 201 Bahk, Y.Y., Lee, H.W., Na, B.K., Kim, J., Jin, K., Hong, Y.S., and Kim, T.S. (2018). Epidemiological Characteristics of Re-emerging Vivax Malaria in the Republic of Korea (1993-2017). Korean J Parasitol 56, 531-543.
[2] Graves, P.M., Gelband, H., and Garner, P. (2015). Primaquine or other 8-aminoquinoline for reducing Plasmodium falciparum transmission. Cochrane Database Syst Rev, CD008152.
[3] Vale, N., Moreira, R., and Gomes, P. (2009). Primaquine revisited six decades after its discovery. Eur J Med Chem 44, 937-953.
[4] Santos, J.B., Luz, F., Deckers, F.A., and Tauil, P.L. (2010). Subdoses of primaquine in overweight patients and malaria vivax relapses: report of two cases in the Federal District, Brazil. Rev Soc Bras Med Trop 43, 749-750.
[5] Baird, J.K., and Hoffman, S.L. (2004). Primaquine therapy for malaria. Clin Infect Dis 39, 1336-1345.
Reference: PAGE () Abstr 9376 [www.page-meeting.org/?abstract=9376]
Poster: Drug/Disease Modelling - Infection