Pharmacokinetic profile of amodiaquine and its active metabolite desethylamodiaquine in Ghanaian patients with uncomplicated falciparum malaria

Table 5 Multivariate analysis of log-transformed Amodiaquine and Desethylamodiaquine pharmacokinetic parameters following artesunate-amodiaquine fixed-dose combination treatment of Ghanaian patients with uncomplicated P. falciparum malaria (geometric Mean Ratios (GMR) and 95% Confidence Intervals (CI))

	GMR	95% CI	p-value	GMR	95% CI	p-value
Area under the Curve (AUC_0-∞)	Amodiaquine (n = 196)			Desethylamodiaquine (n = 210)
Age category: < 1 versus ≥ 5 years	5.42	1.20 to 24.57	0.029	1.12	0.38 to 3.29	0.84
Age category: 1–4 versus ≥ 5 years	1.85	0.60 to 5.71	0.28	0.81	0.36 to 1.79	0.60
Baseline Fever (Temperature: ≥ 37.5 °C)	1.44	1.01 to 2.04	0.045	1.13	0.87 to 1.47	0.37
Underweight-for-age: WAZ < − 2.0 vs WAZ ≥ − 2.0	0.82	0.45 to 1.48	0.50	1.15	0.72 to 1.84	0.55
Underweight-for-age: NA vs WAZ ≥ − 2.0	0.82	0.26 to 2.57	0.74	0.68	0.31 to 1.53	0.35
Dose (mg/kg)	1.04	1.01 to 1.06	0.001	1.02	1.00 to 1.04	0.041
Sex: Female (vs. male)	0.74	0.54 to 1.01	0.058	0.87	0.68 to 1.12	0.28
Parasite density < 100,000 (vs ≥ 100,000/ µL)	0.91	0.58 to 1.42	0.67	1.13	0.81 to 1.58	0.46
Anaemia: Hb < 8.0 g/dL	1.44	0.87 to 2.36	0.15	1.20	0.81 to 1.78	0.35
Site: Navrongo (vs Kintampo)	0.16	0.09 to 0.27	< 0.001	1.12	0.73 to 1.71	0.61
Prior AQ use: Day 0 DEAQ > 20 ng/mL				1.23	0.93 to 1.63	0.14

Maximum concentration (Cmax)	Amodiaquine (n = 217)			Desethylamodiaquine (n = 211)
Age category: < 1 versus ≥ 5 years	2.69	0.83 to 8.73	0.099	0.73	0.26 to 2.00	0.54
Age category: 1–4 versus ≥ 5 years	2.30	0.93 to 5.65	0.071	0.86	0.40 to 1.85	0.69
Baseline Fever (Temperature: ≥ 37.5 °C)	1.57	1.18 to 2.09	0.002	1.17	0.91 to 1.51	0.22
Underweight-for-age: WAZ < -2.0 vs WAZ ≥ − 2.0	0.63	0.38 to 1.05	0.075	1.08	0.69 to 1.70	0.72
Underweight-for-age: NA vs WAZ ≥ − 2.0	0.95	0.38 to 2.36	0.90	0.69	0.32 to 1.51	0.36
Dose (mg/kg)	1.03	1.01 to 1.05	0.001	1.01	1.00 to 1.03	0.14
Sex: Female (vs. male)	0.80	0.62 to 1.05	0.105	0.85	0.67 to 1.07	0.17
Parasite density < 100,000 (vs ≥ 100,000/µL)	0.77	0.53 to 1.13	0.18	1.09	0.79 to 1.50	0.62
Anaemia: Hb < 8.0 g/dL	1.72	1.12 to 2.64	0.013	1.23	0.85 to 1.79	0.27
Site: Navrongo (vs Kintampo)	0.18	0.12 to 0.28	< 0.001	1.36	0.90 to 2.05	0.14
Prior AQ use: Day 0 DEAQ > 20 ng/mL				1.18	0.90 to 1.54	0.23

Apparent Clearance (Cl/f)	Amodiaquine (n = 196)			Desethylamodiaquine (n = 210)
Age category: < 1 versus ≥ 5 years	0.20	0.04 to 0.89	0.035	0.95	0.32 to 2.81	0.92
Age category: 1–4 versus ≥ 5 years	0.55	0.18 to 1.71	0.30	1.27	0.57 to 2.84	0.56
Baseline Fever (Temperature: ≥ 37.5 °C)	0.69	0.49 to 0.99	0.042	0.88	0.67 to 1.15	0.34
Underweight-for-age: WAZ < -2.0 vs WAZ ≥ − 2.0	1.23	0.67 to 2.23	0.50	0.87	0.54 to 1.39	0.56
Underweight-for-age: NA vs WAZ ≥ − 2.0	1.22	0.39 to 3.84	0.73	1.47	0.65 to 3.33	0.35
Dose (mg/kg)	1.00	0.98 to 1.02	0.79	1.01	1.00 to 1.03	0.093
Sex: Female (vs. male)	1.34	0.98 to 1.85	0.070	1.13	0.88 to 1.45	0.34
Parasite density < 100,000 (vs ≥ 100,000/µL)	1.10	0.7 to 1.71	0.69	0.88	0.63 to 1.24	0.46
Anaemia: Hb < 8.0 g/dL	0.70	0.42 to 1.16	0.16	0.83	0.56 to 1.24	0.37
Site: Navrongo (vs Kintampo)	6.82	4.00 to 11.63	< 0.001	0.97	0.63 to 1.50	0.91
Prior AQ use: Day 0 DEAQ > 20 ng/mL				0.81	0.61 to 1.07	0.13

Apparent Volume of distribution (Vd/f)	Amodiaquine (n = 152)			Desethylamodiaquine (n = 209)
Age category: < 1 versus ≥ 5 years	0.62	0.07 to 5.39	0.66	0.74	0.19 to 2.82	0.65
Age category: 1–4 versus ≥ 5 years	0.67	0.11 to 4.21	0.67	0.84	0.32 to 2.19	0.72
Baseline Fever (Temperature: ≥ 37.5 °C)	0.67	0.42 to 1.09	0.10	0.71	0.50 to 1.00	0.050
Underweight-for-age: WAZ < − 2.0 vs WAZ ≥ − 2.0	1.44	0.7 to 2.99	0.32	0.91	0.50 to 1.65	0.76
Underweight-for-age: NA vs WAZ ≥ − 2.0	1.16	0.18 to 7.26	0.88	0.95	0.36 to 2.51	0.91
Dose (mg/kg)	1.01	0.98 to 1.04	0.42	1.02	1.00 to 1.05	0.044
Sex: Female (vs. male)	0.93	0.61 to 1.42	0.74	1.23	0.90 to 1.7	0.20
Parasite density < 100,000 (vs ≥ 100,000/µL)	0.78	0.43 to 1.4	0.41	1.19	0.76 to 1.85	0.45
Anaemia: Hb < 8.0 g/dL	0.54	0.28 to 1.05	0.070	0.75	0.45 to 1.25	0.27
Site: Navrongo (vs Kintampo)	4.30	2.20 to 8.39	< 0.001	0.76	0.44 to 1.31	0.32
Prior AQ use: Day 0 DEAQ > 20 ng/mL				0.86	0.59 to 1.24	0.41

Elimination half-life (t½)	Amodiaquine (n = 152)			Desethylamodiaquine (n = 208)
Age category: < 1 versus ≥ 5 years	1.82	0.59 to 5.6	0.29	1.05	0.49 to 2.21	0.91
Age category: 1–4 versus ≥ 5 years	1.78	0.75 to 4.18	0.19	0.90	0.52 to 1.53	0.69
Baseline Fever (Temperature: ≥ 37.5 °C)	0.95	0.72 to 1.24	0.70	0.85	0.70 to 1.03	0.103
Underweight-for-age: WAZ < − 2.0 vs WAZ ≥ − 2.0	0.98	0.65 to 1.48	0.92	0.95	0.68 to 1.32	0.74
Underweight-for-age: NA vs WAZ ≥ − 2.0	1.39	0.59 to 3.29	0.45	0.84	0.49 to 1.45	0.52
Dose (mg/kg)	1.01	0.99 to 1.02	0.54	1.01	1.00 to 1.02	0.18
Sex: Female (vs. male)	0.74	0.58 to 0.94	0.013	1.08	0.90 to 1.29	0.41
Parasite density < 100,000 (vs ≥ 100,000/µL)	0.84	0.61 to 1.17	0.31	1.41	1.09 to 1.81	0.008
Anaemia: Hb < 8.0 g/dL	0.94	0.64 to 1.36	0.73	0.91	0.69 to 1.21	0.52
Site: Navrongo (vs Kintampo)	0.85	0.58 to 1.24	0.39	0.86	0.63 to 1.16	0.31
Prior AQ use: Day 0 DEAQ > 20 ng/mL				1.08	0.88 to 1.32	0.48

WAZ Weight for Age z-score, NA Not applicable (WAZ score only calculated for children ≤ 5 years), AQ amodiaquine, DEAQ desethylamodiaquine,

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