Article Figures & Data
Figures
- FIG 1
Structure of the PK model of amodiaquine and desethylamodiaquine. Abbreviations: F, oral bioavailability; KTR, first-order transit rate constant; Ka, absorption rate constant; AQ, amodiaquine; DEAQ, desethylamodiaquine; CL, clearance; Vc, central volume of distribution; Q, Q1, and Q2, intercompartmental clearances; Vp, Vp1, and Vp2, peripheral volumes of distribution.
- FIG 2
Visual predictive check of the final model describing the plasma concentrations of amodiaquine (AQ) and desethylamodiaquine (DEAQ) versus time in uncomplicated malaria patients from Thailand (THA), Kenya (KEN), Uganda (UGA), Burkina Faso (BKF), and Ghana (GHA). Open circles are the observed data points; solid and dashed lines are the 50th, 5th, and 95th percentiles of the observed data; shaded areas are the simulated (n = 1,000) 95% confidence interval for the same percentile. The y axis represents the plasma concentration on the log scale. Censored data points below the lower limit of quantification were imputed as LLOQ/2 and included in the calculation of percentiles for the observed and the simulation data. The VPC for amodiaquine for both Thailand and Kenya was cut at times of 90 and 60 h, respectively, since beyond these times the concentrations from both observed and simulated data were below the LLOQ.
- FIG 3
Clearance maturation for amodiaquine (red line) and desethylamodiaquine (blue line) expressed as a fraction of adult clearance predicted from the PK model plotted against postnatal age (assuming that birth occurred at term). The dashed lines indicate the section of the maturation curve that falls in the age range below that observed in the study data and are therefore based on an extrapolation.
- FIG 4
Simulation results of current recommended and optimized dose regimens for amodiaquine. (A and C) Day 7 plasma desethylamodiaquine concentration (A) and maximum concentration of desethylamodiaquine (C) based on the current recommended dose regimen. (B and D) Predicted desethylamodiaquine day 7 concentration for the optimized dose regimen designed to achieve a concentration ≥75% above the threshold value (B) and Cmax of desethylamodiaquine for the optimized dose regimen (D). The black dashed and solid lines in panels A and B are the median and 80% value of median of the simulated day 7 plasma desethylamodiaquine concentration for the typical patient (representing the expected exposure level from the current dosing recommendation), respectively, and the red lines in panels C and D represents the Cmax upper threshold (575 ng/ml). Simulations for each weight are presented as a box plot for the median and 25th and 75th percentiles, with whiskers representing the 5th and 95th percentiles. The boxes in gray indicate that the simulation for that age range is based on an extrapolation, since no PK data for children of that age were available.
Tables
- TABLE 1
Patient characteristics at baselinea
Characteristic Value(s) for the following study(ies): Tarning and colleagues (21, 24) Jullien et al. (23) Mwesigwa et al. (25) Stepniewska et al. (22) Adjei et al. (20) Total No. of patients 26 (+7)b 53 20 61 101 261 % of male patients (no. of male patients/total no. of patients) 0 (0/26) 47.2 (25/53) 65.0 (13/20) 54.1 (33/61) 50.5 (51/101) 46.7 (122/261) Median (range) age (yr) 23.0 (16.0–39.0) 24.0 (18.0–60.0) 9.0 (6.0–13.0) 2.5 (1.0–5.0) 6.0 (1.0–14.0) 7.6 (1.0–60.0) % of patients aged (yr) (no. of patients of the indicated age/total no. of patients): <2 0 (0/26) 0 (0/53) 0 (0/20) 32.8 (20/61) 12.9 (13/101) 12.6 (33/261) 2 to <5 0 (0/26) 0 (0/53) 0 (0/20) 65.6 (40/61) 21.8 (22/101) 23.8 (62/261) 5 to <12 0 (0/26) 0 (0/53) 90.0 (18/20) 1.6 (1/61) 53.5 (54/101) 28.0 (73/261) 12+ 100 (26/26) 100 (53/53) 10.0 (2/20) 0 (0/61) 11.9 (12/101) 34.6 (93/261) % of patients receiving the following drug formulation, treatment regimen (no. of patients receiving the formulation, regimen/total no.): AQ + AS, FDC 0 (0/26) 47 (25/53) 0 (0/20) 47.5 (29/61) 0 (0/101) 20.7 (54/261) AQ + AS, separate tablets 0 (0/26) 53 (28/53) 100 (20/20) 52.5 (32/61) 85.2 (86/101) 63.6 (166/261) AQ alone 100 (26/26) 0 (0/53) 0 (0/20) 0 (0/61) 14.8 (15/101) 15.7 (41/261) Enrollment demographic, vital, and laboratory parameters Median (range) wt (kg) 49.0 (37.0–68.0) 59.0 (39.0–90.0) 24.5 (20.0–42.0) 12.5 (7.0–31.0) 18.0 (6.5–93.0) 21.0 (6.5–93.0) Median (range) total dose (mg/kg) 30.5 (28.1–63.0) 29.5 (18.0–47.1) 24.3 (23.9–26.0) 33.7 (14.8–65.6) 30.0 (30.0–30.0) 30.0 (14.8–65.6) Geometric mean (range) parasitemia (no. of parasites/μl) 1,142 (96–50,453)c 11,923 (1,127–109,356) 11,122 (240–174,800) 23,110 (1,357–467,600) 42,689 (630–566,358) 17,952 (96–566,358) Median (range) hematocrit (%) 32.5 (23.0–40.0) 32.5 (23.0–40.0) Median (range) hemoglobin concn (g/dl) 10.3 (6.7–13.2)d 13.2 (9.9–17.7) 12.2 (9.7–14.1) 8.7 (5.9–12.4) 11.6 (6.5–15.1) 11.2 (5.9–17.7) ↵a Percentages can be more than 100% due to rounding errors. AQ, amodiaquine; AS, artesunate; FDC, fixed-dose combination.
↵b Seven patients were sampled again after delivery, during another episode of malaria.
↵c The data are for patients with vivax malaria.
↵d Derived on the basis of their hematocrit value.
- TABLE 2
Descriptions of population pharmacokinetic and noncompartmental studiesa
Country Study description (authors [reference(s)]) Treatment (protocol) Study population Formulation Manufacturer No. of patients Sampling schedule (protocol) Sample collection Sample storage and assay No. of samples per patientb LLOQ of AQ/DEAQ concn (ng/ml) Thailandc Effect of pregnancy on PK and PD of amodiaquine and desethylamodiaquine (Tarning and colleagues [21, 24]) AQ (10 mg/kg) daily for 3 days, 200 mg amodiaquine hydrochloride (153 mg amodiaquine base) Pregnant women (ages, 16 to 39 yr) in their 2nd and 3rd trimester (with follow-up after delivery) AQ alone Sanofi-Aventis, France 26 (7)d 0, 4, 24, 28, 48, 48.5, 49, 50, 51, 52, 54, 56, 58, and 72 h; 4, 5, 7, 14, 21, 28, 35, and 42 days A sample was drawn from a catheter during the first 3 days and thereafter by venous puncture and placed into lithium heparin tubes Samples were stored at −20°C and analyzed by LC-MS/MS 14/22 (14/22) 1/2 Kenyac Efficacy of fixed vs nonfixed dose of ASAQ (Jullien et al. [23]) Two tablets of AS-AQ at a fixed dose (100/270 mg) or 4 tablets of AS (50 mg) + 4 tablets of AQ (153 mg) daily for 3 days, 353/200 mg amodiaquine hydrochloride (153/270 mg amodiaquine base) Adults (ages, 18 to 60 yr) AS + AQ at a fixed dose and as a loose formulation Sanofi-Aventis, France 53 Before 1st dose, 15 min to 4 h after 1st dose, 15 min to 4 h after 2nd dose, just before 3rd dose, 15 min to 4 h after 3rd dose, days 7, 14, 21, and 28 Samples were analyzed by HPLC 4/8 1/1 Ugandae Determine PK parameters for AS and AQ in children (Mwesigwa et al. [25]) AS (50-mg tablets at 4 mg/kg twice a day for 3 days) + AQ (200-mg tablets at 10 mg/kg once a day on the first 2 days and 5 mg/kg on the third day), 200 mg amodiaquine hydrochloride (153 mg amodiaquine base) Children (ages, 5 to 13 yr) AS + AQ, loose formulation Sanofi-Aventis, France 20 Just prior to 3rd dose and at 2, 4, 8, 24, and 120 h after 3rd dose A venous sample was drawn into potassium oxalate-sodium fluoride tubes Samples were stored at −80°C and analyzed by LC-MS/MS 2/6 5/5 Burkina Fasoc Compare bioavailability of fixed doses of AS and AQ vs AS and AQ separately (Stepniewska et al. [22]) AS-AQ at a fixed dose (one dose of 25/67.5 mg/kg for children <12 mo of age or two doses for children ages 12 to 60 mo) or AS (50-mg tablet, a half tablet for children <12 mo of age and one tablet for children ages 12 to 60 mo) + AQ (153 mg, a half tablet for children <12 mo of age and one tablet for children ages 12 to 60 mo) daily for 3 days, 200 mg amodiaquine hydrochloride (153 mg amodiaquine base) Children (ages, 1 to 5 yr) AS + AQ at a fixed dose and as a loose formulation Sanofi-Aventis, France 61 Before the 1st dose, 4 h after the 3rd dose, and then at days 7 and 14 and days 21 and 28 A venous sample was collected in lithium heparin tubes Samples were stored at −20°C and analyzed by LC-MS/MS 2/3 1/1 Ghanac Compare the effect of AS on AQ (comparison between AQ and loose formulations of AS and AQ) (Adjei et al. [20]) AQ (10-mg/kg single dose) or AS (4-mg/kg single dose) + AQ (10-mg/kg single dose) daily for 3 days, 200 mg amodiaquine hydrochloride (153 mg amodiaquine base) Children (ages, 1 to 14 yr) AS + AQ, loose formulation Pfizer, Dakar, Senegal 101 Before the dose on days 3 and 7 A venous sample was collected into heparinized polypropylene tubes Samples were stored at −20°C and analyzed by HPLC 1/2 10/10 ↵a All samples were venous plasma. AS, artesunate; AQ, amodiaquine; LLOQ, lower limit of quantification; DEAQ, desethylamodiaquine; LC-MS/MS, liquid chromatography-tandem mass spectrometry; HPLC, reverse-phase high-performance liquid chromatography.
↵b Median number of amodiaquine/desethylamodiaquine samples per subject; values in parentheses are for the same women at 3 months postdelivery.
↵c Population PK study.
↵d The same women were sampled again at 3 months postdelivery during another malaria episode.
↵e Noncompartmental pharmacokinetic analysis.
- TABLE 3
Parameter estimates of the population pharmacokinetic model for amodiaquine and desethylamodiaquinef
Drug and parameter Typical valuea BSV or BOVa,b Value (% RSE) 95% CI BSV (% RSE) BOV (% RSE) % shrinkage 95% CI Eta Epsilon Amodiaquine Ka (1/h) 0.589 (23) 0.409, 0.905 78.5 (12) 41.7 62.0, 96.5 MTT (h) 0.236 (26) 0.161, 0.334 93.4 (16) 61.8 60.6, 120 NN 2.00 (78) 1.09, 6.31 F 1 Fixed 30.9 (8.0) 27.1 26.5, 36.0 CLAQc (liters/h) 2,960 (4.4) 2,600, 3,118 32.2 (13) 44.3 24.2, 39.5 VcAQc (liters) 13,500 (19) 7,423, 17,824 53.1 (30) 55.4 19.4, 79.5 QAQc (liters/h) 2,310 (9.2) 1,877, 2,722 VpAQc (liters) 22,700 (10) 17,956, 27,114 Additive errord (ng/ml) LLOQ/5 + 0.445 (19) LLOQ/5 + 0.249, 0.609 26.7 Proportional error (%) 19.9 (11) 16.1, 24.6 Desethylamodiaquine CLDEAQc (liters/h) 32.6 (2.9) 29.7, 33.4 20.0 (10) 31.3 15.5, 23.5 VcDEAQc (liters) 258 (12) 201, 318 67.2 (21) 59.3 36.0, 89.2 Q1DEAQc (liters/h) 154 (6.6) 131, 171 Vp1DEAQc (liters) 2,460 (5.9) 2,129, 2,677 Q2DEAQc (liters/h) 31.3 (6.2) 26.8, 34.3 Vp2DEAQc (liters) 5,580 (4.3) 4,968, 5,904 Additive errord (ng/ml) LLOQ/5 Fixed 16.5 Proportional error (%) 24.2 (4.0) 22.2, 25.9 Covariate effects PMA50 for AQe (time [mo] from conception) 11.8 (4.6) 10.50, 12.70 Hill factor for AQe 3.6 (4.0) 3.23, 3.80 PMA50 for DEAQe (time [mo] from conception) 12.9 (5.7) 11.60, 14.30 Hill factor for DEAQe 3.22 (4.7) 2.85, 3.43 Effect of first dose on F (%) −22.4 (19) −32.0, −15.6 ↵a The precision of the parameter estimates was assessed using a nonparametric bootstrap of the final model (n = 500). The relative standard errors were calculated as 100 × (standard deviation/mean), while the confidence intervals were obtained on the basis of the empirical percentiles of the bootstrap estimates.
↵b Between-subject and between-occasion variability were assumed to be log-normally distributed and are reported as the approximate percent coefficient of variation.
↵c All clearances and volumes of distribution refer to a patient weighing 50 kg, the median weight in the data set.
↵d For the data contributed by each study, the additive error was fixed to 20% of the lower limit of quantification (LLOQ) in that study plus an estimated parameter. For desethylamodiaquine, this extra parameter was not significantly different from zero, so the additive error was fixed to the lower bound of LLOQ/5.
↵e Estimated using prior functionality in NONMEM.
↵f Abbreviations: AQ, amodiaquine; DEAQ, desethylamodiaquine; BSV, between-subject variability; BOV, between-occasion variability; RSE, relative standard error; Ka, absorption rate constant; MTT, mean transit time; NN, number of transit compartments; F, relative bioavailability; CL, clearance; Vc, central volume of distribution; Q, Q1, and Q2, intercompartmental clearances; Vp, Vp1, and Vp2, peripheral volumes of distribution; PMA50, time to reach 50% of clearance maturation; Hill factor, steepness of the clearance maturation curve.
- TABLE 4
Current dose regimen and optimized dose regimen based on simulations for amodiaquine
Current manufacturer dose regimen Proposed dose regimen Body wt (kg) No. of tablets/day, tablet strength Total amodiaquine dose (mg) Body wt (kg) No. of tablets/day, tablet strength (mg) Total amodiaquine dose (mg) 4 to 8 1, 67.5 67.5 4 to 6a 1, 67.5 67.5 9 to 17 1, 135 135 7 to 10b 1, 135 135 18 to 35 1, 270 270 11 to 16 1.5, 135c 202.5 ≥36 2, 270 540 17 to 28 2.5, 135c 337.5 29 to 49 2, 270 540 ≥50 3, 270 810 ↵a A substantial number of simulated patients (78%) in this weight band were younger (<1 year) than those available in the data set.
↵b A proportion of the simulated patients (38%) in this weight band were younger (<1 year) than those available in the data set.
↵c In these weight bands, as an alternative to splitting tablets, one could suggest using tablets of different strengths. Either option is viable, according to the preference of the caregiver.
Supplemental material
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Supplemental Figures S1 and S2
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