Table 1.
Study 1: Mean multiple-dose plasma pharmacokinetic parameters of racemic mefloquine, mefloquine enantiomers and carboxylic acid metabolite, and ritonavir for the three treatments: ritonavir alone (period 1), mefloquine alone (period 2), and ritonavir with mefloquine (period 3)
| Parameter | Treatment* Ritonavir and mefloquine (Period 3) | Drug alone (Period 1 or 2) | anova for longitudinal design Point estimate (90% CI)† (%) | P value | Pooled Intra-subject %CV | Pooled Inter-subject %CV |
|---|---|---|---|---|---|---|
| Ritonavir | ||||||
| AUC(0,12 h) (µg ml−1 h) | 19.4 ± 9.3 | 27.5 ± 11.7 | 68.8 (55.7–84.9) | 0.011 | 25.3 | 51.6 |
| Cmax (ng ml−1) | 3463 ± 1842 | 5063 ± 2468 | 63.5 (47.1–85.6) | 0.022 | 36.2 | 57.1 |
| C0 (ng ml−1) | 739 ± 499 | 1288 ± 1001 | 57.0 (41.3–78.6) | 0.012 | 39.3 | 114 |
| C12 (ng ml−1) | 585 ± 259 | 714 ± 446 | 88.1 (68.9–113) | 0.366 | 29.6 | 44.3 |
| t1/2,z (h)‡ | 3.1 ± 0.8 | 3.1 ± 0.7 | 100 (89.1–113) | 0.950 | 13.2 | 18.2 |
| CL/F (ml min−1) | 229 ± 146 | 146 ± 76.1 | 145 (118–180) | 0.011 | 25.3 | 51.6 |
| tmax (h) | 4.0 (2.0, 5.0) | 4.0 (3.0, 5.0) | 0 h | 0.05 | 15.1 | 8.2 |
| fu (%) | 0.43 ± 0.19 | 0.45 ± 0.15 | 93.5 (65.4–134) | 0.735 | 47.8 | ne |
| Mefloquine | ||||||
| AUC(0,168 h) (µg ml−1 h) | 140 ± 26.7 | 144 ± 30.7 | 98.0 (91.6–105) | 0.598 | 9.1 | 17.7 |
| Cmax (ng ml−1) | 1211 ± 210 | 1212 ± 312 | 101 (93.1–110) | 0.795 | 11.4 | 17.6 |
| C0 (ng ml−1) | 664 ± 167 | 699 ± 217 | 95.7 (86.0–107) | 0.471 | 14.6 | 23.3 |
| C168 (ng ml−1) | 689 ± 143 | 664 ± 167 | 105 (95.0–115) | 0.411 | 13.2 | 20.3 |
| CL/F (ml min−1) | 30.6 ± 5.6 | 30.1 ± 5.3 | 102 (95.4–109) | 0.598 | 9.1 | 17.7 |
| (+)-RS Mefloquine | ||||||
| AUC(0,168 h) (µg ml−1 h) | 34.6 ± 7.2 | 33.5 ± 7.0 | 103 (96.7–111) | 0.388 | 9.2 | 17.0 |
| Cmax (ng ml−1) | 326 ± 64.4 | 341 ± 94.3 | 97.3 (88.3–107) | 0.613 | 13.1 | 18.4 |
| C0 (ng ml−1) | 128 ± 40.0 | 152 ± 62.5 | 88.3 (70.1–111) | 0.351 | 32.1 | 26.5 |
| C168 (ng ml−1) | 171 ± 46.8 | 128 ± 40.0 | 134 (116–156) | 0.005 | 20.7 | 20.5 |
| CL/F (ml min−1) | 62.4 ± 11.6 | 64.5 ± 12.3 | 96.7 (90.4–104) | 0.388 | 9.2 | 17.0 |
| (–)-SR Mefloquine | ||||||
| AUC(0,168 h) (µg ml−1 h) | 106 ± 23.3 | 109 ± 26.5 | 96.7 (90.5–103) | 0.391 | 9.1 | 19.9 |
| Cmax (ng ml−1) | 895 ± 195 | 902 ± 246 | 100 (90.9–110) | 0.984 | 13.1 | 19.7 |
| C0 (ng ml−1) | 533 ± 141 | 544 ± 165 | 98.3 (89.3–108) | 0.755 | 13.0 | 24.4 |
| C168 (ng ml−1) | 524 ± 127 | 533 ± 141 | 98.8 (90.0–109) | 0.826 | 12.7 | 23.3 |
| CL/F (ml min−1) | 20.5 ± 4.1 | 19.8 ± 3.7 | 103 (96.7–111) | 0.391 | 9.1 | |
| AUC SR/AUC RS | 3.1 ± 0.6 | 3.3 ± 0.6 | 93.6 (90.2–97.0) | 0.007 | 4.9 | 16.4 |
| MMQ | ||||||
| AUC(0,168 h) (µg ml−1 h) | 244 ± 82.6 | 254 ± 119 | 99.4 (92.5–107) | 0.875 | 9.7 | 40.6 |
| Cmax (ng ml−1) | 1835 ± 700 | 1791 ± 831 | 104 (98.0–111) | 0.247 | 8.3 | 38.0 |
| C0 (ng ml−1) | 1403 ± 543 | 1436 ± 609 | 98.4 (89.3–108) | 0.770 | 13.3 | 41.5 |
| C168 (ng ml−1) | 1422 ± 556 | 1403 ± 543 | 102 (92.2–112) | 0.772 | 13.3 | 40.1 |
| AUC MMQ/AUC MFQ | 1.81 ± 0.76 | 1.85 ± 0.94 | 101 (93.5–110) | 0.764 | 11.0 | 50.7 |
MFQ, mefloquine; MMQ, mefloquine carboxylic acid metabolite; CI, confidence interval; ne, not estimable.
Ritonavir pharmacokinetic measurements were taken after the 13th ritonavir dose (200 mg every 12 h for 7 days, 13 doses) alone and with mefloquine after the 7th dose of mefloquine (250 mg daily for 3 days then weekly for 4 weeks, 7 doses). Mefloquine pharmacokinetic measurements were taken after the 6th mefloquine dose alone and with ritonavir after the 7th mefloquine dose. Values of treatment means are expressed as arithmetic mean ± s.d. (n = 10, ritonavir, except n = 11 for tmax, t1/2,z and fu; n = 12, mefloquine, MMQ and enantiomers); tmax values are expressed as medians (with minimum and maximum given in parentheses)
Percentage ratio of the least-squares geometric treatment mean of the coadministered treatment in period 3 relative to that of the drug-alone treatment in period 1(ritonavir) or 2 (mefloquine). The value for tmax is the point estimate of the absolute difference in medians, relative to the drug-alone treatment. The level of significance was set at 0.05.
Harmonic means are 2.9 h for both arms.