The Malaria Eradication Research Agenda (malERA) Consultative Group on Drugs present a research and development agenda to ensure that appropriate drugs are available for use in malaria eradication.

A method is described for the simultaneous determination of the carboxylic acid and N‐acetyl‐derivatives of primaquine, in plasma and urine. After oral administration of 45 mg primaquine, to five healthy volunteers, absorption was rapid, with peak primaquine levels of 153.3 +/‐ 23.5 ng/ml at 3 +/‐ 1 h, followed by an elimination half‐life of 7.1 +/‐ 1.6 h, systemic clearance of 21.1 +/‐ 7.1 l/h, volume of distribution of 205 +/‐ 371 and cumulative urinary excretion of 1.3 +/‐ 0.9% of the dose. Primaquine underwent rapid conversion to the carboxylic acid metabolite of primaquine, which achieved peak levels of 1427 +/‐ 307 ng/ml at 7 +/‐ 4 h. Levels of this metabolite were sustained in excess of 1000 ng/ml for the 24 h study period, and no carboxyprimaquine was recovered in urine. N‐acetyl primaquine was not detected in plasma or urine. Following [14C]‐primaquine administration to one subject, plasma radioactivity levels rapidly exceeded primaquine concentrations. Plasma radioactivity was accounted for mainly as carboxyprimaquine . Though 64% of the dose was recovered over 143 h, as [14C]‐radioactivity in urine, only 3.6% was due to primaquine. As neither carboxyprimaquine nor N‐ acetylprimaquine were detected in urine, the remaining radioactivity was due to unidentified metabolites.

1 Plasma concentrations of halofantrine (Hf) and its putative principal plasma metabolite desbutyl halofantrine (Hfm) have been measured in two separate studies after oral administration of the hydrochloride salt. 2 Six healthy male volunteers each received single oral doses of 250, 500 and 1000 mg administered after an overnight fast. A washout period of at least 6 weeks was allowed between each dose. A further 250 mg single oral dose was administered to the same six subjects in a fasting state and after a standardised fatty meal in a randomised study, again with a washout period of at least 6 weeks. 3 AUC and maximum plasma concentration (Cmax) for Hf increased in proportion to the dose from 250-500 mg. This increase was non-proportional when the dose was increased from 500 to 1000 mg. For Hfm, in the dose range 250-500 mg, AUC but not Cmax increased in proportion in the increase in dose size. The increase in these parameters was nonproportional when the dose was increased from 500 to 1000 mg. Time to reach peak concentrations for Hf and Hfm and the elimination half-life of Hf remained unchanged across the dosage range. 4 Following a fatty meal, Cmax for Hf was increased from 184 ± 115 ,ug 1-1 (fasting) to 1218 ± 464 ,ug 1-1 (fed). AUC for Hf was increased from 3.9 ± 2.6 mg l-1 h (fasting) to 11.3 ± 3.5 mg 1-1 h following a fatty meal. The AUC for Hfm was also increased from 8.8 ± 3.5 mg I-1 h (fasting) to 10.7 ± 3.2 mg 1-1 h (fed). 5 Hf was not detected in urine, and -0.01% of the dose was present as Hfm. 6 These data suggest that after oral administration of Hf hydrochloride, linear pharmacokinetics are observed in the single dose range of 250-500 mg. The apparent non-linearity above 500 mg may be a function of the poor solubility of Hf. 7 The relative systemic availability of Hf is increased significantly in the presence of food of high fat content. The mechanism responsible for this effect and its clinical consequences remain to be established.

1 The pharmacokinetics of primaquine have been examined in five healthy volunteers who received single oral doses of 15, 30 and 45 mg of the drug, on separate occasions. Each subject received an i.v. tracer dose of [14C]-primaquine (7.5 ,uCi), simultaneously with the 45 mg oral dose. 2 Absorption of primaquine was virtually complete with a mean absolute bioavailability of 0.96 ± 0.08. 3 Elimination half-life, oral clearance and apparent volume of distribution for both primaquine and the carboxylic acid metabolite were unaffected by either dose size, or route of administration. 4 The relationships between area under the curve and dose size were linear for both primaquine (r = 0.99, P -0.01) and its carboxylic acid metabolite (r = 0.99, P , 0.01). 5 The mean whole blood to plasma concentration ratios were determined for primaquine (0.81), and for the carboxylic acid metabolite of primaquine (0.84). 6 Primaquine is a low clearance compound (CL = 24.2 ± 7.4 1 h-1), is extensively distributed into body tissues (V = 242.9 ± 69.51) and is not subject to extensive first pass metabolism.

The activation of the antimalarial drug proguanil (PG) to the active metabolite cycloguanil (CG) has been evaluated in a panel of 18 subjects. These subjects had previously been screened and classified as mephenytoin poor (PMm) or extensive metabolisers (EMm) and sparteine poor (PMs) or extensive metabolisers (EMs). Five subjects had the phenotype PMm/EMs, one was PMm/PMs, six subjects were EMm/PMs and six were EMm/EMs. The PG/CG ratio in urine (8 h) was significantly higher in PMm than in EMm (P = 0.0013). This study shows that the P450-isozyme involved in the polymorphic oxidation of mephenytoin is of critical importance in the activation of PG to CG and this may explain the large intersubject variability in CG concentrations in man. PMm make up about 3% of Caucasians, but up to about 20% of Orientals. From the present study, it may be anticipated that the antimalarial effect of PG is absent or impaired in this phenotype. The sparteine polymorphism appeared not to influence the activation of PG to CG significantly.

1. Based on the ratio of drug to active metabolite excreted in urine approximately 3% of a healthy Caucasian population showed a reduced ability to convert proguanil to cycloguanil. 2. Pharmacokinetic analysis showed that this observation resulted from a reduced oral clearance of proguanil in these individuals (245, 534 and 552 ml min‐1) compared with the rest of the population (858 +/− 482 ml min‐1). 3. Peak plasma concentrations of active metabolite were significantly lower in these subjects (54.2, 26.8 and 51.7 ng ml‐1) compared with the rest of the population (141 +/− 45.2 ng ml‐1). 4. The observed variability may result from the polymorphic metabolism of proguanil in man.

1 The pharmacokinetics of artemether were investigated (a) in six healthy male Thai volunteers after single 200 mg oral doses and (b) in eight male Thai patients with acute uncomplicated falciparum malaria after an initial 200 mg oral dose followed by 100 mg at 12 h then 100 mg daily for 4 days. 2 In the healthy subjects, median (range) maximum plasma concentrations of artemether of 118 (112-127) ng ml-' were reached at 3 (1-10) h. Thereafter, drug concentrations declined monoexponentially with a median (range) t,.z of 3.1 (1.0-9.6) h. The median (range) AUC and MRT values were 1.10 (0.33-4.44) ,ug ml-l h and 8.3 (3.5-20.8) h. The median Cmax value of dihydroartemisinin, an active metabolite, was 379 (162-702) ng ml-' at 6 (2-12) h. Its median AUC value was 6.6 (0.83-38.7) P,g ml-' h; the apparent t,,, was 10.6 (4.7-19.2) h and the median MRT value was 16.0 (5.0-41.0) h. 3 In the patients, a higher Cmax value of parent drug than those observed in healthy subjects (median and range of 231 (116-411) ng ml-l), was reached at 3 (1-3) h after the first dose. Steady state was reached after the third dose (24 h) and concentrations fluctuated over the range of 36-60 ng ml-'. The respective median (range) values of AUC and t,,z were 5.8 (3.76-12.9) ,ug ml-l h and 4.2 (2.5-5.3) h. Compared with the parent compound, dihydroartemisinin reached higher peak concentrations at later times (Cmax: 593 (483-729) ng ml-1; tmax 7.4 (3-20) h). The high concentrations were sustained until the final dose of artemether (96 h). The t,,z of 12.5 (9.9-21.2) h was significantly longer than that of the parent drug and AUC was significantly greater (49.6 (29.0-60.5) ,ug ml-l h). 4 All patients showed a rapid initial response to treatment with median values for fever clearance time (FCI) and parasite clearance time (PCT) of 30 and 36 h, respectively.However, one patient recrudesced on day 19 after treatment. Cmax and the AUC of artemether and dihydroartemisinin in this patient were lower than those in other patients (116 ng ml-l and 29.0 ,ug ml-l h).

1. The metabolism of proguanil to the active metabolite cycloguanil has been evaluated in 135 British Troops and 26 Kenyan schoolchildren. 2. Large inter‐subject variability was observed in both plasma and urinary concentrations of proguanil and cycloguanil after standard doses of drug. 3. Based on the ratio of proguanil to cycloguanil (P/C) in urine the British troops formed a non‐normal distribution. 90% of the population formed a discrete distribution with P/C ranging from 0.5 to 9.0 while the remaining 10% were scattered throughout the distribution to an extreme value of 39. A similar pattern of variability was observed using P/C from a 6 h plasma sample. 4. This variability was due to differences in the ability of individuals to metabolise proguanil to cycloguanil. 5. Thirteen schoolchildren who had experienced malaria during prophylaxis with proguanil and thirteen matched controls each received proguanil (100 mg). We could not discriminate between the two groups based on P/C ratio in either a 6 h plasma or 0‐6 h urine sample.