1. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients
- Author
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Julie A. Simpson, Piero Olliaro, Sornchai Looareesuwan, Tsiri Agbenyega, Raymond Miller, François Nosten, Michèle van Vugt, Isabela Ribeiro, Srivicha Krudsood, Malcolm E. Molyneux, Sharif Mahsuf Mansor, Karen I. Barnes, Sanjeev Krishna, Helen McIlleron, Lorrin Pang, James Mwenechanya, Gianni Di Perri, Nicholas J. White, Madalitso Tembo, Kris Weerasuriya, V. Navaratnam, Kyaw N. Win, Melba Gomes, Peter I. Folb, Steve A. Ward, Division of Clinical Pharmacology, Faculty of Health Sciences, and Infectious diseases
- Subjects
Male ,Aging ,medicine.medical_treatment ,Artesunate ,lcsh:Medicine ,Parasitemia ,Pharmacology ,Gastroenterology ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacology/Drug Discovery ,Child ,Asia, Southeastern ,Drug absorption ,Volume of distribution ,0303 health sciences ,wc_770 ,Medicine in Developing Countries ,General Medicine ,Venous blood ,Middle Aged ,Artemisinins ,3. Good health ,Treatment Outcome ,Infectious Diseases ,Child, Preschool ,Drugs and adverse drug reactions ,Female ,Drug therapy ,Sesquiterpenes ,Research Article ,Adult ,medicine.medical_specialty ,Adolescent ,030231 tropical medicine ,Dihydroartemisinin ,qv_38 ,Pharmacokinetic analysis ,03 medical and health sciences ,Antimalarials ,Sex Factors ,Pharmacokinetics ,Administration, Rectal ,Internal medicine ,Malarial parasites ,parasitic diseases ,medicine ,Humans ,Dosing ,Demography ,Salvage Therapy ,030306 microbiology ,business.industry ,Suppositories ,lcsh:R ,Infant ,Body weight ,medicine.disease ,R1 ,Malaria ,chemistry ,Africa ,business - Abstract
Background Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria. Methods and Findings Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36–1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent of any confounders. No associations between the parasitological responses and the posterior individual estimates of V/F, CL/F, and AUC0–6h were observed. Conclusions The pharmacokinetic properties of DHA were affected only by gender and body weight. Patients with the lowest area under the DHA concentration curve did not have slower parasite clearance, suggesting that rectal artesunate is well absorbed in most patients with moderately severe malaria. However, a number of modelling assumptions were required due to the large intra- and inter-individual variability of the DHA concentrations., A study of the population pharmacokinetics of intra-rectal artesunate in patients with moderately severe falciparum malaria found the pharmacokinetic properties of dihydroartemisinin were affected only by gender and body weight., Editors' Summary Background. More than 40% of the world's population is at risk of malaria, a tropical parasitic disease that is transmitted between people by infected mosquitoes. Malaria parasites cause a 'flu-like illness that includes chills, fevers, headaches, and sometimes nausea and vomiting. If untreated, people with malaria can rapidly become anemic—the parasite destroys their red blood cells—or can develop complications that damage the brain and other organs. Severe malaria can be fatal and must be treated quickly. It has become a matter of great concern that the parasite has developed resistance to most of the drugs used to treat or prevent malaria. In the past few years, artemisinin derivatives have been shown to be an effective new form of treatment. Artemisinin derivatives are effective, rapid-acting antimalarial drugs—wormwood, the plant source of artemisinin, is an ancient Chinese cure for malaria. Artesunate, a water-soluble derivative of artemisinin, can be given as tablets or as injections. However, people with severe malaria often cannot take oral medicines, and in rural settings in the developing world, artesunate injections are usually impracticable. Consequently, rectal artesunate suppositories have been developed to provide first-line treatment of severe malaria in these settings. This simple dosing method can “buy” patients valuable time during which they can be moved to a hospital for further treatment. Why Was This Study Done? When treating severe malaria, it is important that every patient absorbs the antimalarial drug rapidly and efficiently into their blood. If even a small proportion of patients malabsorb the drug, many people could die. How the body processes a drug is known as pharmacokinetics, and although some pharmacokinetic studies have investigated how the body processes artesunate given in rectal suppositories, relatively little is know about the population pharmacokinetics of artesunate given this way. That is, the patient characteristics that affect the processing of intra-rectal artesunate are not known, and it is unclear whether a small proportion of the population might fail to absorb the drug given via this route. In this study, the researchers have developed and tested a population pharmacokinetic model for artesunate given rectally to children and adults with moderately severe malaria. What Did the Researchers Do and Find? The researchers took serial blood samples from nearly 200 patients with moderately severe malaria in Africa and Southeast Asia for the first 24 hours after they received a rectal artesunate suppository. They measured the levels of artesunate and dihydroartemisinin (DHA; the body rapidly converts artesunate to DHA, which kills the malaria parasites) in these samples and used these data to build a pharmacokinetic model for how the body processes. Averaged out across the patients, they calculated, for example, that half of the drug present absorbed was eliminated within 43 minutes. To find out whether any patient characteristics affected the pharmacokinetics of intra-rectal artesunate, the researchers used their model to estimate the clearance of DHA from the body and the ability of DHA to spread through the body (so-called apparent volume of distribution) for the study patients. This analysis showed that only gender and weight affected DHA pharmacokinetics. Finally, the researchers showed that how well the parasite was cleared from the patients was not related to these pharmacokinetic parameters, although the need for earlier rescue treatment was associated with a larger volume of distribution for DHA. Importantly, the parasitological response was not affected by the estimated cumulative amount of DHA absorbed into the blood during the first six hours after treatment. What Do These Findings Mean? The data presented in this study indicate that individual patients processed artesunate very differently in terms of how they absorbed the drug and how it spread around the body. Even so, the maximal effects of artesunate on the malaria parasite were achieved rapidly in nearly all the patients. This and other pharmacokinetic findings must be interpreted with caution, warn the researchers, because their model included many assumptions to allow, for example, for the variability of DHA concentrations both within individual patients and between patients. Nevertheless, the findings provide important clues about which patient characteristics might cause early treatment failure, and indicate that artesunate is sufficiently well absorbed via the rectal route in most patients to make artesunate suppositories a promising first-line treatment for moderately severe malaria. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030444. • World Health Organization links to general information on malaria plus specific information on rectal artesunate • MedlinePlus encyclopedia entry on malaria • US Centers for Disease Control and Prevention information on malaria for patients and professionals • Wikipedia pages on malaria and artemisinin (note that Wikipedia is a free online encyclopedia that anyone can edit)
- Published
- 2016