lunes, 21 de octubre de 2013

Primaquine Failure and Cytochrome P-450 2D6 in Plasmodium vivax Malaria — NEJM

Primaquine Failure and Cytochrome P-450 2D6 in Plasmodium vivax Malaria — NEJM


Primaquine Failure and Cytochrome P-450 2D6 in Plasmodium vivax Malaria

N Engl J Med 2013; 369:1381-1382October 3, 2013DOI: 10.1056/NEJMc1301936
Article

To the Editor:

Primaquine is the only medication approved by the Food and Drug Administration to eradicate the hypnozoites of Plasmodium vivax, but relapses of P. vivax malaria due to drug failure occur.1 Human cytochrome P-450 isoenzyme 2D6 (CYP2D6) may be a key enzyme involved in metabolizing primaquine into redox-active metabolites against hypnozoites in the liver.2,3 As part of a phase 1 clinical trial of a vaccine against P. vivax (Study of VMP001 and AS01B in Healthy Malaria-Naive Adults; ClinicalTrials.gov number, NCT01157897), 33 participants were exposed to P. vivax sporozoites from the bites of infected mosquitoes. Parasitemia developed in all participants by day 13 after the challenge, and parasitemia rapidly cleared on initiation of the directly observed administration of a combination of chloroquine (at a dose of 1500 mg base by mouth over a period of 48 hours) and primaquine (at a dose of 30 mg by mouth daily for 14 days). Two participants (6%) had multiple relapses of malaria (see Fig. 1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). After each relapse, parasitemia was rapidly cleared in these participants with chloroquine (at a standard dose of 1500 mg base by mouth over a period of 48 hours) and a weight-based dose of primaquine (at a total dose of 6 mg per kilogram of body weight). To our knowledge, true resistance to primaquine in P. vivax hypnozoites has not been described; this suggests a role for host factors in drug failure.1 We sought to identify an association between CYP2D6 activity and primaquine drug failure. CYP2D6 phenotypes were ascertained in 25 available participants. The institutional review boards of the Walter Reed Army Institute of Research, the Naval Medical Research Center, and the Walter Reed Army Medical Center, as well as the Western Institutional Review Board approved the study, and all participants provided written informed consent. CYP2D6 phenotyping was performed; 21 participants had an extensive-metabolizer phenotype (at least one allele coding for an enzyme with normal activity) (84%), 3 participants had an intermediate-metabolizer phenotype (heterozygous for one null and one reduced-function allele) (12%), and 1 participant had a poor-metabolizer phenotype (two nonfunctional alleles) (4%)4,5 (Table 1 in the Supplementary Appendix). There were no relapses in the extensive-metabolizer group, two relapses in one participant in the intermediate-metabolizer group, and three relapses in the one participant in the poor-metabolizer group (Table 1Table 1Episodes of Malaria Relapse up to 20 Months after Challenge, According to CYP2D6 Activity Phenotype.). Although the sample size was small, there were significant associations between low-activity CYP2D6 phenotypes and the initial relapse and number of relapses up to 20 months after the challenge (Table 1). Plasma concentrations of the parent primaquine were measured in most of these participants for 24 hours after oral administration of 30 mg of primaquine. Participants with relapse had significantly decreased clearance of primaquine and the highest residual plasma concentrations after 24 hours (Fig. 2 and Table 2 in the Supplementary Appendix). This effect, which was consistent with decreased metabolism by CYP2D6, was most apparent in Participant 1 (who had the poor-metabolizer phenotype) and Participant 2 (who had the intermediate-metabolizer phenotype) (Fig. 2 in the Supplementary Appendix). These data support our hypothesis that a primaquine metabolite responsible for hypnozoite killing is generated by a CYP2D6-dependent pathway. We propose that these persons have polymorphisms in CYP2D6 resulting in diminished metabolism of primaquine such that sufficient levels of the active metabolite were not achieved. These data suggest that host genetics may contribute to primaquine failure in persons who have relapse of P. vivax malaria. Larger study populations are necessary to further elucidate the relationships among CYP2D6 activity, geographic regional dosing requirements, and clinical failure of primaquine to eradicate P. vivax hypnozoites.
Jason W. Bennett, M.D. Brandon S. Pybus, Ph.D. Anjali Yadava, Ph.D. Donna Tosh, R.N. Jason C. Sousa, Ph.D. Walter Reed Army Institute of Research, Silver Spring, MD William F. McCarthy, Ph.D. U.S. Army Medical Materiel Development Activity, Frederick, MD Gregory Deye, M.D. Victor Melendez, Ph.D. Christian F. Ockenhouse, M.D., Ph.D. Walter Reed Army Institute of Research, Silver Spring, MD
Supported by the Military Infectious Diseases Research Program and the Program for Appropriate Technologies in Health Malaria Vaccine Initiative. The views expressed in this letter are those of the authors and do not necessarily reflect the official policy or positions of the U.S. Department of the Army, the Department of Defense, or the U.S. government. The authors report being employees of the U.S. government. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
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