Table 4. Population parameter estimates from the simultaneous pharmacokinetic lumefantrine/desbutyl-lumefantrine drug-metabolite model.

Parameter	Fixed effects		Random effects
	Population estimate (BS estimate)	%RSE (95% CI parameter estimate)	%CV for IIV (BS estimate)	%RSE (95% CI parameter estimate)
F	1 (fixed)	—	57.9 (57.2)	57.2 (49.0 to 64.9)
Box–Cox shape parameter on F	−0.449 (−0.459)	35.5 (−0.793 to −0.126)	—	—
ka (h−1)	0.0409 (0.0422)	13.3 (0.0349 to 0.0567)	—	—
CLLF/F (l/h)	1.56 (1.57)	6.24 (1.40 to 1.77)	—	—
VC LF/F (l)	21.2 (21.6)	19.5 (14.6 to 30.5)	111 (110)	110 (87.5 to 134)
QLF/F (l/h)	0.381 (0.387)	11.3 (0.313 to 0.497)	—	—
VP LF/F (l)	53.8 (54.5)	8.60 (46.2 to 65.2)	—	—
CLDLF/F (l/h)	78.4 (77.4)	7.80 (64.6 to 88.5)	38.8 (39.8)	39.8 (32.0 to 51.0)
VC DLF/F (l)	2,470 (2,560)	13.1 (1,960 to 3,280)	86.0 (82.3)	82.3 (49.5 to 110)
QDLF/F (l/h)	104 (103)	13.2 (78.3 to 131)	34.9 (33.8)	33.8 (0.339 to 53.0)
VP DLF/F (l)	8,650 (8,870)	14.2 (6,990 to 11,800)	47.7 (45.3)	45.3 (0.453 to 68.9)
Dose50 (mg/kg) on F	3.86 (fixed)	—	—	—
Pregnancy on ka	0.513 (0.543)	52.4 (0.264 to 0.889)	—	—
Parasitaemia on F	−0.226 (−0.218)	81.8 (−0.557 to 0.156)	—	—
σLF	0.251 (0.251)	11.8 (0.196 to 0.315)	—	—
σDLF	0.0560 (0.0559)	8.46 (0.0467 to 0.0657)	—	—

Coefficient of variation (%CV) for inter-individual variability (IIV) was calculated as $100\times \sqrt{{\mathrm{e}}^{\mathrm{e}\mathrm{s}\mathrm{t}\mathrm{i}\mathrm{m}\mathrm{a}\mathrm{t}\mathrm{e}}-1}$. The relative standard error (%RSE) was calculated as $100\times \frac{\mathrm{S}\mathrm{t}\mathrm{a}\mathrm{n}\mathrm{d}\mathrm{a}\mathrm{r}\mathrm{d}\mathrm{d}\mathrm{e}\mathrm{v}\mathrm{i}\mathrm{a}\mathrm{t}\mathrm{i}\mathrm{o}\mathrm{n}}{\mathrm{A}\mathrm{v}\mathrm{e}\mathrm{r}\mathrm{a}\mathrm{g}\mathrm{e}\mathrm{p}\mathrm{a}\mathrm{r}\mathrm{a}\mathrm{m}\mathrm{e}\mathrm{t}\mathrm{e}\mathrm{r}\mathrm{e}\mathrm{s}\mathrm{t}\mathrm{i}\mathrm{m}\mathrm{a}\mathrm{t}\mathrm{e}}$ from 1,000 iterations of a non-parametric bootstrap (BS) procedure. The 95% confidence interval (95% CI) is displayed as the 2.5th to 97.5th percentile of the BS estimate, and the BS estimate as the average value.

LF: lumefantrine; DLF: desbutyl-lumefantrine; F: relative bioavailability; Box–Cox shape parameter: shape parameter on Box–Cox transformation; k_a: absorption rate constant; V_C/F: apparent central volume of distribution; V_P/F: apparent peripheral volume of distribution; Q/F: inter-compartmental clearance; CL/F: elimination clearance; and σ: residual error additive on log scale. All parameters were centred around a non-pregnant patient with an admission parasitaemia of 15,800 parasites/μl, and clearance and volume parameters were centred around a non-pregnant patient weighing 42 kg and scaled allometrically ($\mathrm{C}\mathrm{L}/Q=\mathrm{\theta }\left(n\right)\times {\frac{\mathrm{W}\mathrm{T}}{42}}^{\frac{3}{4}},V=\mathrm{\theta }\left(n\right)\times \frac{\mathrm{W}\mathrm{T}}{42}$); parasitaemia was coded as in its logarithm in an exponential relationship centred around the mean ($F=\mathrm{\theta }\left(n\right)\times {\mathrm{e}}^{{\mathrm{\theta }}_{\mathrm{p}\mathrm{a}\mathrm{r}\mathrm{a}\mathrm{s}\mathrm{i}\mathrm{t}\mathrm{a}\mathrm{e}\mathrm{m}\mathrm{i}\mathrm{a}}-(\mathrm{p}\mathrm{a}\mathrm{r}\mathrm{a}\mathrm{s}\mathrm{i}\mathrm{t}\mathrm{a}\mathrm{e}\mathrm{m}\mathrm{i}\mathrm{a}-4.2)}$), and a categorical pregnancy effect on k_a was coded as follows: k_a = θ × (1 + θ_pregnant).

Pregnancy was a categorical/proportional covariate on F [1 + θ], dose₅₀ was implemented using a saturation model on F [1 − (Dose/(θ + Dose))], and admission parasitaemia was implemented using a power relationship on F [(parasitaemia/median value)^θ].