Although the population pharmacokinetics (popPK) approach can accommodate sparse data and provide information on the impact of covariates, it requires the use of sophisticated software, which may not be available to everyone. A comparison of the popPK approach with NPD offers no real advantages when determining PK parameters from small sample sizes [
22]. Therefore, the NPD approach was used. The characteristics of the study participants are shown in Table
1. The PK parameters for MQ, obtained from the concentration–time profile shown in Fig.
1 are compared with parameters from similar studies (Table
2). A recent study: Rich and population pharmacokinetics of mefloquine intermittent preventive treatment for malaria in pregnancy in Gabon (Ramharter et al. pers comm) was also conducted as part of a multicentre trial (NCT 00811421) with parameters included in Table
2. Relative to the area-under-the-curves (AUCs) from the Gabon trial and Na Bangchang et al. [
10], the data suggest HIV-infected pregnant women taking CTX may result in enhanced MQ bio-availability. Future studies using a population-based analysis would be better able to determine which parameter is responsible for the suggested interaction. The terminal elimination half-life (t
1/2 = 12.0 days) was similar to the mean half-life of 11.6 days for whole blood MQ in pregnant women given 125 or 250 mg per week during the third trimester of pregnancy [
9].
Plasmodium falciparum-infected pregnant and non-pregnant Thai women showed more rapid whole blood MQ half-lives of 7.2 and 8.1 days, respectively [
10]. In comparison, the half-life for whole blood MQ in healthy individuals was reported to be 13.8 days [
21], while plasma half-lives range from 16 to 28 days [
23‐
29]. The systemic clearance (CL/
f) determined from this study was 0.035 l/h/kg. The AUC
0→∞ of 431 µg-h/ml determined from the study was higher than that reported from healthy pregnant women (~300 µg-h/ml) and pregnant women infected with
P. falciparum (319 µg-h/ml) [
9,
10]. The observed t
max and C
max were 4 h and 974 ng/ml and within the range of values reported from normal pregnant women (t
max = 6, range 3–34 h) and
P. falciparum pregnant women given 15 mg/kg of mefloquine (C
max = 1257, range 650–1584 ng/ml) [
9,
10]. The t
max and C
max determinations are heavily biased since the first sample was collected at 4 h and presents a limitation of the study design. The MQ levels at 7 days post second dose of 594 ± 80 ng/ml (mean ± SE, n = 16) was not significantly different (p = 0.4) from levels at 7 days post first dose (490 ± 99 ng/ml, n = 11), indicating no significant drug accumulation. Although at three half-lives, some accumulation can be expected, large inter-individual variability as well as a small sample size may account for the lack of significant drug accumulation.
Table 1
Characteristics of subjects upon enrolment
Age (years) | 27 (17–42) | 27 (17–42) |
Body weight (kg) | 57 (40–77) | 60 (42–80) |
Gestation (weeks) | 20 (8–28) | 20 (8–28) |
Haemoglobin (mg/dL) | 10.3 (5.6–15.2) | 10.6 (5.7–13.7) |
Table 2
Comparison of pharmacokinetic parameters for mefloquine
Present study | Whole blood | Pregnant | 15 mg/kg | 974 | 12.0 | 14.4 | 0.035 | 431 |
Ramharter et al. (pers comm) | Whole blood | Pregnant | 15 mg/kg | 577a
| 16.8 | 30.4b
| 0.073b
| 308a
|
| Whole blood | Males | 1000 | 800 | 13.8 | 13.3 | 0.066 | 648 |
| Plasma | African males | 1000 | 954 | 20.0 | 14.8 | 0.020 | – |
Caucasian males | 1000 | 990 | 27.5 | 20.3 | 0.025 | |
| Plasma | Males | 1000 | | 21.6 | 23.2 | 0.031 | 587 |
| Whole blood | Pregnant (P. falciparum) | 15 mg/kg | 1257 | 7.2 | 10.8 | 0.047 | 319 |
Whole blood | Non-pregnant Females (P. falciparum) | 15 mg/kg | 1617 | 8.1 | 10.0 | 0.043 | 349 |
| Whole blood | Pregnant | 250 mg/week | – | 11.6 | – | 0.047 | – |
125 mg/week | | | | | |