Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda

Table 2 Parameter estimates for the final simultaneous artemether and dihydroartemisinin model

Parameter	Population estimate^a	95% CI^b	IIV[%CV]^a	95% CI^b
Parameter	(% RSE)^b	95% CI^b	(% RSE)^b	95% CI^b
CL_ARM/F (L/hr)	875 (18.7)	625-1280	28.0 (47.6)	12.0-37.8
V_ARM/F (L)	2160 (17.4)	1620-3100	-	-
CL_DHA/F (L/hr)	468 (10.2)	387-588	90.4 (39.0)	40.5-126
V_DHA/F (L)	57.1 (20.1)	41.7-88.8	-	-
MTT (hr)	0.274 (19.4)	0.174-0.378	75.2 (39.6)	41.4-121
DUR (hr)	0.687 (25.5)	0.380-1.14	151 (24.1)	90.6-209
F	1 (fixed)	-	85.5 (24.8)	53.2-108
No. of transit compartments	6 (fixed)	-	-	-
σ	0.166 (6.87)	0.130-0.221	23.1 (51.7)	8.35-35.2
Post-hoc estimates parameters ^c	Artemether Median (range)	Dihydroartemisinin Median (range)
AUC_60h-∞ (hr × ng/mL)	111 (16.2-317)	167 (55.3-437)
C_MAX (ng/mL)	32.9 (7.5-82.8)	45.2 (14.1-114)
T_MAX (hr)	1.16 (0.65-3.81)	1.37 (0.82-3.89)

^aPopulation mean values and inter-individual variability (IIV) estimated by NONMEM. IIV is presented as 100* ((e^{mean variance estimate})-1)^1/2.
^bThe relative standard error (RSE) is calculated as 100*(standard deviation/mean value) from 1,046 successful iterations of a non-parametric bootstrap. The 95% confidence interval (95% CI) is displayed as the 2.5 to 97.5 percentiles of the bootstrap estimates.
^cPost-hoc estimates were calculated as the median and ranges of the empirical Bayes estimates.
CL_ARM/F: elimination clearance of artemether, V_ARM/F: apparent volume of distribution of artemether, CL_DHA/F: elimination clearance of dihydroartemisinin, V_DHA/F; apparent volume of distribution of dihydroartemisinin, MTT; mean transit time, DUR; duration of zero order-absorption and F; relative bioavailability. The additive error (σ) variance will essentially be exponential on artithmic scale data. AUC: total area under the plasma concentration-time curve after the last dose, C_MAX: maximum concentration after the last dose and T_MAX: Time to maximum concentration.

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