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Model Farmakokinetik/Farmakodinamik Populasi Primakuin dan Analisis Faktor Genetik Enzim CYP2D6 Terkait Kejadian Relaps Malaria Vivaks = Population Pharmacokinetics/pharmacodynamics Model of Primaquine and Analysis of CYP2D6 Enzyme Genetic Factors Associated with the Relapse Event of Vivax Malaria.

Relaps masih menjadi masalah dalam eradikasi malaria vivaks. Primakuin adalah satu-satunya antihipnozoit yang saat ini tersedia di pasaran. Efikasi primakuin dipengaruhi oleh farmakokinetik dan farmakodinamik obat. Kemampuan CYP2D6 memetabolisme primakuin menjadi bentuk aktif akan memengaruhi kadar primakuin dan efikasi klinisnya. Pada studi ini dilakukan analisis farmakokinetik dan farmakodinamik primakuin dengan pendekatan populasi pada subjek dengan malaria vivaks; serta dianalisis hubungan variasi jumlah copy gen CYP2D6 dengan kejadian relaps. Subjek studi adalah 174 orang Tentara Nasional Indonesia yang terinfeksi malaria vivaks dan diterapi dengan kombinasi skizontisida dan primakuin selama 14 hari. Kejadian relaps diamati selama satu tahun. Model farmakokinetikfarmakodinamik primakuin dikembangkan dengan metode non-linear mixed effect menggunakan piranti lunak NONMEM versi 7.4.1. Kuantifikasi jumlah copy gen CYP2D6 dilakukan pada 49 subjek. Jumlah copy gen ditentukan berdasarkan nilai Cq hasil amplifikasi intron 6 dengan real-time qPCR. Jumlah copy dihitung sesuai dengan rumus 2 -∆∆Cq x jumlah copy DNA kalibrator, ∆∆Cq = ∆Cq (kalibrator)  ∆Cq (sampel) dan ∆Cq = Cq (CYP2D6) – Cq (RNAse P). Hubungan jumlah copy gen CYP2D6 dan kejadian relaps malaria vivaks dianalisis dengan uji Chi-square. Hasil penelitian menunjukkan bahwa kadar primakuin plasma paling baik dideskripsikan oleh model satu kompartemen dengan first order absorption. Berat badan diimplementasikan sebagai fungsi alometrik pada clearance (CL) dan volume distribusi (Vd). Piperakuin maupun pironaridin menurunkan CL dan Vd primakuin sebesar 3354%. Faktor genetik CYPD6 tidak memengaruhi CL primakuin. Risiko kejadian relaps malaria vivaks dideskripsikan dengan model constant hazard pada model time-to-event. Peningkatan satu point activity score gen CYP2D6 menurunkan risiko relaps sebesar 88,3%, sehingga dapat disimpulkan bahwa karakteristik genetik CYP2D6 menjadi salah satu faktor yang dapat memengaruhi risiko relaps malaria vivaks. Tidak didapatkan hubungan antara AUC primakuin dan kejadian relaps, sehingga hasil ini tidak dapat digunakan untuk menghitung dosis optimal primakuin. Kuantifikasi jumlah copy gen CYPD6 dilakukan pada 21 subjek relaps dan 28 subjek kontrol. Mayoritas subjek memiliki jumlah copy ≥ 2 (39 dari 49 orang). Tidak didapatkan hubungan antara jumlah copy gen CYP2D6 dan kejadian relaps (p = 0,155).
Kata kunci: copy number variation, CYP2D6, non-linear mixed effect model, NONMEM, primakuin


Relapse event is still a problem in vivax malaria eradication. Primaquine is the only antihypnozoite in the market. Efficacy of primaquine might be influenced by pharmacokinetics and pharmacodynamics of the drug and CYP2D6 enzyme activity which metabolizes primaquine to become active metabolite. In this study, we analyzed the pharmacokinetics and pharmacodynamics of primaquine using population approach and the association between CYP2D6 gene copy numbers and relapse events. Subjects of this study were 174 Indonesian army members with vivax malaria infection and treated with combination of schizonticide and primaquine for 14 days. Relapse events were observed for one year. The pharmacokineticspharmacodynamics model of primaquine was developed using non-linear mixed effect method with NONMEM software version 7.4.1. Forty-nine subjects were included on CYP2D6 gene copy number quantification. Copy number was determined based on Cq value as a result of intron 6 amplification using real-time qPCR. Copy number was quantified using formula 2 -∆∆Cq x copy number of CYP2D6 gene DNA calibrator, where ∆∆Cq = ∆Cq (calibrator)  ∆Cq (sample) and ∆Cq = Cq (CYP2D6) – Cq (RNAse P). The association between CYP2D6 gene copy number and relapse event was analyzed using Chi-square test. As a result, primaquine concentrations were best described by one compartment model with first order absorption. Body weight was implemented as allometric function on clearance (CL) and distribution volume (Vd) of primaquine. Piperaquine and pyronaridine decreased 33─54% of CL and Vd of primaquine. CYP2D6 genetic factors might not influence CL of primaquine. Relapse risk of vivax malaria was best described by constant hazard model on time-to-event model. The one point increment of CYP2D6 gene activity score decreased 88,3% of the relapse risk. It can be concluded that the CYP2D6 gene charateristics is determinant factor of relapse risk. There was no association between AUC of primaquine and relapse event. This result can not be used to quantify optimal dose of primaquine. Quantification of CYP2D6 gene copy number was done on 21 relapsers and 28 control subjects. Most subjects have ≥ 2 copies (39 out of 49 subjects). There was no association between copy number of CYP2D6 gene and relapse event (p = 0,155).
Keywords: copy number variation, CYP2D6, non-linear mixed effect model, NONMEM, primaquine