Table 5.
Miltefosine: primary and secondary pharmacokinetic parameters
| Study | Patients | Weight (kg) | Daily dose | C ss a (µg/mL) | k a (day−1) | t max (h) | V central/F (L) | CL/F (L/day) | V peripheral/F (L) | Q (L/day) | AUCb (µg·day/mL) | t ½ (days) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Non-compartmental | ||||||||||||
| Berman [61] | NA | NA | NA | 70c | NA | 8–24 | NA | NA | NA | NA | NA | 150–200 h |
| Castro et al. [100] | Adult cutaneous leishmaniasis patients | 70.84 ± 11.73 | 2.11 ± 0.32 mg/kg/day, 28 days | 31.9 (17.2–42.4) | NA | NA | NA | NA | NA | NA | 628 (213–861) 880 (427–1206)d |
34.4 (9.5–46.15) |
| Paediatric cutaneous leishmaniasis patients | 26.22 ± 7.62 | 2.27 ± 0.16 mg/kg/day, 28 days | 22.7 (17.0–29.3) | NA | NA | NA | NA | NA | NA | 448 (304–583) 652 (438–832)d |
37.1 (7.4–47.0) | |
| Compartmental | ||||||||||||
| Dorlo et al. [70] | Cutaneous leishmaniasis patients | 85 (70–113) | 150 mg, 28 days | 30.8 (median) | 8.64 (10.1%)e
IIV: 24.2% |
NA | 39.6 (4%) IIV: 18.3%f |
3.87 (5.3%) IIV: 23.2%f |
1.65 (12.4%) | 0.0375 (22.0%) | NA | 7.05 (5.45–9.10) Terminal t ½: 30.9 (30.8–31.2) |
| Dorlo et al. [71] | Paediatric visceral leishmaniasis patients | 15 (9–23) | 1.5–2.5 mg/kg, 28 days | NA | 9.98 (11.5%)g
IIV: 18.4% |
NA | 40.1 (4.5%)h
IIV: 34.1%f |
3.99 (3.5%)h
IIV: 32.1%f |
1.75 (8.2%) | 0.0347 (18.3%) | NA |
t
½ (range): 4.99–7.18 Terminal t ½: 35.5 |
| Adult visceral leishmaniasis patients | 36 (16–58) | 50–150 mg, 3–6 week | ||||||||||
| Cutaneous leishmaniasis patientsi | 85 (70–113) | 150 mg, 28 days | ||||||||||
| Dorlo et al. [72]j | Nepalese VL patents | 40 (8–56) | Adults: >25 kg: 100 mg, ≤25 kg: 50 mg, 28 days Children: 2.5 mg/kg, to nearest 10 mg, 28 days |
35.3 (11.6–120) | NA | NA | 38.5 (4.5%)h
IIV: 31.6%f |
3.69 (3.4%)h
IIV: 35.1%f |
1.69 (8.6%) | 0.0316 (16.6%) | 724 (265–2260) 1140 (340–4200)d |
6.26 (4.18–9.27) Terminal t ½: 48.9 (48.6–51.0) |
Data given as either median (range) or mean (coefficient of variation %), unless indicated otherwise
Trough concentration (Ctrough) not available for miltefosine
AUC area under the concentration–time curve, CL clearance, C ss steady-state concentration, F bioavailability, IIV inter-individual variability, k a absorption rate constant, NA not available, Q intercompartmental clearance, t max time to C max within one dosing interval, V volume of distribution, t ½ plasma elimination half-life, V central volume of distribution of the central compartment, V peripheral volume of distribution of the peripheral compartment, VL visceral leishmaniasis
aMiltefosine accumulates during treatment and reaches C ss during the last week of treatment
bAUCD28 (AUC from start to end of treatment) unless indicated otherwise
cUnclear whether this is the mean C ss or the maximum C ss
dAUC from start of treatment to infinity (AUC∞)
eReported as 0.36 h−1
fIIV of clearance and volume of central compartment were correlated
gReported as 0.416 h−1
hParameter scaled to a standardised fat-free mass of 53 kg. This corresponds to a theoretical weight of 70 kg
iSame patients as described in Dorlo et al. [70]
jParameters estimated with data of Nepalese VL patient cohort and additional information on previously described cohorts (Dorlo et al. [70]/Dorlo et al. [71])