Table 1. The therapeutic capacity of a range of antimalarial drugs, quantified by their PRRtot.
| Drug | PRRtot(simple method) | PRRtot (PKPD method) | Monotherapy cure rate (PKPD method) |
|---|---|---|---|
| Partner drugs (sensitive): | |||
| AQ | (103)15/2 = 1022.5 | 1.7 × 1020 | 86% |
| LF | (103)24.5/2 ≈ 1037 | 2.7 × 1035 | 90% |
| MQ | (103)28/2 = 1042 | 1.3 × 1056 | 94% |
| PPQ | (103)22/2 = 1033 | 3.2 × 1031 | 80% |
| SP | (102)46/2 = 1046 | n/a | n/a |
| Partner drugs (resistant): | |||
| PPQR | (103)8/2 = 1012 | 3.2 × 1013 | 55% |
| SPR | (102)9/2 = 109 | n/a | n/a |
| Artemisinins: | |||
| ARq.d. | 1012 | 4.8 × 1012 | 57.4% |
| ARb.i.d | 1020 | 1.2 × 1026 | 91.8% |
| AS | 1012 | 7.6 × 1010 | 43.2% |
| DHA | 1012 | 5.0 × 1010 | 35.3% |
The “simple” method uses Equation 1 for partner drugs, Equation 2 for artemisinins given once-daily over three days, and Equation 3 for artemether when given as six twice-daily doses. The PKPD method uses the approach outlined in Equation 4 and we include the partner drug monotherapy cure rates to quantify the degree of their drug sensitivity/resistance. The PRRtot for the PKPD method are the median values shown in Fig. 1a (note that we cannot currently undertake a PKPD analysis of SP for reasons given in the Supplementary Information File). The PKPD method assumes wide, but continuous, ranges of values for the key PK and PD parameters (see Supplementary Information File) which results in the distributions of PRRtot values on Fig. 1(a). This gives rise to an apparent discrepancy in this table i.e. that AQ has a lower therapeutic capacity (PRRtot) than PPQ but higher monotherapy cure rate. The reason is that PRRtot given in the table is the median of the distribution simulated (Fig. 1(a)) whereas cure rates depend on the proportion of patients with low PRRtot. Patients given AQ in our parametrisation have relatively tightly clustered PRRtot values which means the proportion of patients with a low PRRtot is small (see 5th centile values on Fig. 1(a)) so its failure rate is lower than for PPQ.
Abbreviations: AQ = amodiaquine, AR = artemether, AS = artesunate, DHA = dihydroartemisinin, LF = lumefantrine, MQ = mefloquine, n/a = not applicable, PKPD = pharmacokinetic-pharmacodynamic modelling, PPQ = piperaquine, SP = sulfadoxine-pyrimethamine;. Subscripts: b.i.d = twice daily dosing, R = resistance, q.d. = once daily dosing.