Is there a differential conversion of artesunate to dihydroartemisinin in pregnant vs. post‐partum patients with malaria after oral artesunate dosing?

Artesunate (AS) is widely used for the treatment of uncomplicated malaria and is prescribed with agents such as amodiaquine, mefloquine or sulfadoxime‐pyrimethamine in the treatment protocols 1. The conversion of AS to its active metabolite, dihydroartemisinin (DHA) is considered very vital for its antimalarial activity 1. The conversion of AS to DHA occurs via mechanisms such as simple non‐enzymatic gut pH hydrolysis, cleavage in blood influenced by esterases and by cytochrome P450 (CYP) 2A6 isoform 2. The disposition of DHA is governed by an effective phase 2 conjugation by UDP‐glucuronosyltransferase (UGT) 1A9 and UGT2B7 expressed in the gastro‐intestinal tract and liver 3.

The report of Kloprogge et al., using a well‐defined population model in pregnant patients, has unambiguously confirmed that malaria disease and pregnancy produced opposite effects on the oral bioavailability of AS. While the malarial disease increased the bioavailability of AS by approximately 87%, pregnancy reduced the bioavailability of AS by approximately 23% 4. These data are clearly suggestive that exposures (i.e. AUC(0,12 h) to both AS and DHA are increased in post‐partum women as compared with the exposure in pregnant women. In order to explain the decreased exposure of AS and DHA during pregnancy, the authors have postulated two hypotheses which included: a) lowered bioavailability of AS due to increased presystemic CYP activity during pregnancy and b) higher clearance of DHA due to increased UGT 2B7 activity in pregnant women 4. However due to a small effect size it was difficult to ascertain the significance of higher clearance of DHA in pregnant vs. post‐partum patients 4. Therefore, an important question arises on the necessity of AS dose adjustment for the treatment of malaria during pregnancy.

The work of Kloprogge et al. is very informative and provides the right platform for further introspection to mitigate the AS therapy failures during pregnancy due to reduced bioavailability of AS 4. However, one important aspect that appears to have been neglected in this population model was to model and examine unequivocally the conversion of AS to DHA on a molar basis during pregnancy vs. the post‐partum phase of the study 4. A quick examination of the mean AUC data of AS and DHA obtained in this study (without adjustments using respective molecular weights) suggested that the DHA (AUC(0,12 h) : AS (AUC(0,12 h) ratios were similar between the pregnant phase (12.15 to 12.33) vs. post‐partum phase (11.61 to 13.55) 4. Therefore, the key question that needs consideration is whether or not the presystemic and/or systemic conversion of AS to DHA is different between pregnant vs. post‐partum patients.

In order to address this dilemma, two other recent reports were examined to find a commonality to decipher the question on the conversion of AS to DHA 5, 6. In the first report, McGready et al. reported the pharmacokinetics of AS and DHA in pregnant and post‐partum patients 5. The computed mean DHA : AS AUC(0,∞)ratios in this study were 8.94 (pregnant women) vs. 14.62 (post‐partum women) suggesting a possibility of a higher conversion of AS to DHA in post‐partum patients 5. In the second report, Valea et al. reported the pharmacokinetics of AS and DHA when co‐administered with mefloquine in two separate cohorts (pregnant women and non‐pregnant women) 6. The computed mean DHA : AS AUC(0,t) ratios in this study were 15.89 (pregnant women) vs. 21.83 (non‐pregnant women) suggesting a possibility of a higher conversion of AS to DHA in pregnant women 6. Furthermore, using the clinical pharmacokinetic data of both AS and DHA compiled by Morris et al. (2011) that included healthy subjects, adult (males and non‐pregnant women), and paediatric patients suffering from uncomplicated malaria, an overall average DHA : AS AUC ratio of 11.04 was computed for all the studies 7. While there are limitations in the above comparisons with respect to health status, population type, ethnicity, dose size of AS, presence of co‐administered anti‐malarial drugs, differences in pharmacokinetic sampling schemes etc. 5, 6, 7, it is evident based on the reports of McGready et al. 5 and Valea et al. 6 that pregnant women tend to convert less AS into DHA. However, the report of Kloprogge et al. 4 suggested the DHA : AS AUC ratios in pregnant women (12.15 to 12.33) may be in line with those observed for the population at large (11.04) 7.

In summary, it may be important to ascertain whether or not the conversion of AS to DHA is influenced by the pregnancy status in patients with malaria. This may be particularly important for two reasons: a) the increase in dose size of AS may not necessarily translate into higher DHA exposure if there is a limitation in the conversion of AS to DHA during pregnancy and b) if there is no impediment in the conversion of AS to DHA during pregnancy, it may influence the calibration of the AS dose to mitigate the risk of lower bioavailability of AS. Lastly, although a bit speculative in nature, is there a possibility of a fraction of the oral AS dose that remains unabsorbed during pregnancy leading to lower bioavailability of AS and a lesser conversion of AS to DHA?

Competing Interests

The author has completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf. The author declares no support from any organization for the submitted work. The author declares no other relationships or activities that could appear to have influenced the submitted work.

Srinivas, N. R. (2016) Is there a differential conversion of artesunate to dihydroartemisinin in pregnant vs. post‐partum patients with malaria after oral artesunate dosing?. Br J Clin Pharmacol, 81: 389–390. doi: 10.1111/bcp.12809.