Limits...
Population Pharmacokinetics and Antimalarial Pharmacodynamics of Piperaquine in Patients With Plasmodium vivax Malaria in Thailand.

Tarning J, Thana P, Phyo AP, Lwin KM, Hanpithakpong W, Ashley EA, Day NP, Nosten F, White NJ - CPT Pharmacometrics Syst Pharmacol (2014)

Bottom Line: Piperaquine pharmacokinetics were described well by a three-compartment distribution model.The results suggest that a large proportion of the first relapses were suppressed completely by residual piperaquine concentrations and that recurrences resulted mainly from emergence of the second or third relapse or from reinfection.This suggests a significant reduction in P. vivax morbidity when using dihydroartemisinin-piperaquine compared with other antimalarial drugs with shorter terminal postprophylactic effects.

View Article: PubMed Central - PubMed

Affiliation: 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

ABSTRACT
Dihydroartemisinin-piperaquine is an effective drug in the treatment of Plasmodium falciparum and P. vivax malaria. The objective of this study was to evaluate the population pharmacokinetics and pharmacodynamics of piperaquine in patients with P. vivax malaria in Thailand after a standard regimen of dihydroartemisinin-piperaquine to determine whether residual piperaquine prevents or delays the emergence of P. vivax relapse. Sparse blood samples were collected from 116 patients. Piperaquine pharmacokinetics were described well by a three-compartment distribution model. Relapsing P. vivax malaria was accommodated by a constant baseline hazard (8.94 relapses/year) with the addition of a surge function in a fixed 3-week interval and a protective piperaquine effect. The results suggest that a large proportion of the first relapses were suppressed completely by residual piperaquine concentrations and that recurrences resulted mainly from emergence of the second or third relapse or from reinfection. This suggests a significant reduction in P. vivax morbidity when using dihydroartemisinin-piperaquine compared with other antimalarial drugs with shorter terminal postprophylactic effects.

No MeSH data available.


Related in: MedlinePlus

Relationship between piperaquine treatment and risk of relapsing P. vivax malaria infections. (a) Mean hazard rate of relapsing P. vivax malaria versus time in the presence (solid line) and absence (dashed line) of a standard piperaquine treatment (primary y-axis). The frequency of observed recurrent P. vivax infections for all patients in the efficacy study (241 patients, Table 1) is displayed on the secondary y-axis. The hazard of the first relapse (3 weeks) is completely suppressed and the hazard of the second relapse (6 weeks) is almost completely suppressed after piperaquine treatment. The model-predicted hazard rate after piperaquine treatment is in agreement with the observed frequency of observed recurrent P. vivax infections. (b) Simulated day-7 venous piperaquine plasma concentrations and chance of remaining malaria free for 30 days. Open gray circles represent simulated patients. Solid black line represents the 50th percentile and dash lines represent the 5th and 95th percentiles of the prediction interval. The dashed vertical line indicates the predicted day-7 concentration that results in 99% chance of remaining malaria free for 30 days for a typical patient.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4150927&req=5

fig4: Relationship between piperaquine treatment and risk of relapsing P. vivax malaria infections. (a) Mean hazard rate of relapsing P. vivax malaria versus time in the presence (solid line) and absence (dashed line) of a standard piperaquine treatment (primary y-axis). The frequency of observed recurrent P. vivax infections for all patients in the efficacy study (241 patients, Table 1) is displayed on the secondary y-axis. The hazard of the first relapse (3 weeks) is completely suppressed and the hazard of the second relapse (6 weeks) is almost completely suppressed after piperaquine treatment. The model-predicted hazard rate after piperaquine treatment is in agreement with the observed frequency of observed recurrent P. vivax infections. (b) Simulated day-7 venous piperaquine plasma concentrations and chance of remaining malaria free for 30 days. Open gray circles represent simulated patients. Solid black line represents the 50th percentile and dash lines represent the 5th and 95th percentiles of the prediction interval. The dashed vertical line indicates the predicted day-7 concentration that results in 99% chance of remaining malaria free for 30 days for a typical patient.

Mentions: The individual patient parasite burden (Table 1) corresponded approximately to a total of 1011 parasites in a typical adult at admission. This assumes that P. vivax does not sequester substantially. DHA-PQ is administered for 3 consecutive days, covering two asexual cycles. Assuming a parasiticidal effect (parasite reduction ratio) of a 10,000-fold parasite reduction per cycle by dihydroartemisinin (without any additional effect by piperaquine) results in a 100,000,000-fold reduction in total parasite biomass during the first two cycles.20 At an initial parasite burden of 1011 parasites, this would leave ~1,000 parasites to be eliminated by residual piperaquine concentrations to prevent recrudescent malaria. Piperaquine alone has not been adequately assessed in P. vivax malaria, but if it is similar to chloroquine, it should provide parasite reduction ratios of ~100 to 1,000 per cycle, so most patients should be parasite free 6–8 days post-treatment if piperaquine levels are sufficient to sustain a maximum parasiticidal effect for this time. If the parasite burden is not eliminated completely, then these remaining parasites can multiply and cause a recrudescent infection. However, a high cure rate of the asexual infection is likely in this study as concentrations of piperaquine after the second asexual cycle (i.e., ≥ 4 days) are highly likely to be able to eliminate ~1,000 parasites. In the first relapse of tropical P. vivax malaria (unaffected by drugs and assuming 1–10 schizonts and a subsequent parasite multiplication rate of ~10 per cycle), the hypnozoite-derived hepatic schizonts must liberate 13–17 days after the onset of the primary illness to produce a symptomatic infection at day 21. However, if residual piperaquine concentrations are sufficiently high, they could suppress and eliminate the asexual parasites derived from 10,000 to 100,000 released merozoites and thereby prevent the first relapse completely. If residual piperaquine concentrations are not sufficiently high for complete elimination, they could cause an initial suppression, resulting in a delayed symptomatic first relapse. Only 14% (15 out of 109) of recurrent P. vivax infections occurred before day 39, which suggests that DHA-PQ treatment prevents a large proportion of the first relapses (Figure 4). The majority of infections (64%, 70 out of 109) occurred between day 42 and 56, suggesting that these are mainly delayed second relapses (Figure 4). There will be some contribution from reinfections, but as entomological inoculation rates are probably well below 0.5/person/year for P. vivax in this area, this contribution is likely to be small.


Population Pharmacokinetics and Antimalarial Pharmacodynamics of Piperaquine in Patients With Plasmodium vivax Malaria in Thailand.

Tarning J, Thana P, Phyo AP, Lwin KM, Hanpithakpong W, Ashley EA, Day NP, Nosten F, White NJ - CPT Pharmacometrics Syst Pharmacol (2014)

Relationship between piperaquine treatment and risk of relapsing P. vivax malaria infections. (a) Mean hazard rate of relapsing P. vivax malaria versus time in the presence (solid line) and absence (dashed line) of a standard piperaquine treatment (primary y-axis). The frequency of observed recurrent P. vivax infections for all patients in the efficacy study (241 patients, Table 1) is displayed on the secondary y-axis. The hazard of the first relapse (3 weeks) is completely suppressed and the hazard of the second relapse (6 weeks) is almost completely suppressed after piperaquine treatment. The model-predicted hazard rate after piperaquine treatment is in agreement with the observed frequency of observed recurrent P. vivax infections. (b) Simulated day-7 venous piperaquine plasma concentrations and chance of remaining malaria free for 30 days. Open gray circles represent simulated patients. Solid black line represents the 50th percentile and dash lines represent the 5th and 95th percentiles of the prediction interval. The dashed vertical line indicates the predicted day-7 concentration that results in 99% chance of remaining malaria free for 30 days for a typical patient.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150927&req=5

fig4: Relationship between piperaquine treatment and risk of relapsing P. vivax malaria infections. (a) Mean hazard rate of relapsing P. vivax malaria versus time in the presence (solid line) and absence (dashed line) of a standard piperaquine treatment (primary y-axis). The frequency of observed recurrent P. vivax infections for all patients in the efficacy study (241 patients, Table 1) is displayed on the secondary y-axis. The hazard of the first relapse (3 weeks) is completely suppressed and the hazard of the second relapse (6 weeks) is almost completely suppressed after piperaquine treatment. The model-predicted hazard rate after piperaquine treatment is in agreement with the observed frequency of observed recurrent P. vivax infections. (b) Simulated day-7 venous piperaquine plasma concentrations and chance of remaining malaria free for 30 days. Open gray circles represent simulated patients. Solid black line represents the 50th percentile and dash lines represent the 5th and 95th percentiles of the prediction interval. The dashed vertical line indicates the predicted day-7 concentration that results in 99% chance of remaining malaria free for 30 days for a typical patient.
Mentions: The individual patient parasite burden (Table 1) corresponded approximately to a total of 1011 parasites in a typical adult at admission. This assumes that P. vivax does not sequester substantially. DHA-PQ is administered for 3 consecutive days, covering two asexual cycles. Assuming a parasiticidal effect (parasite reduction ratio) of a 10,000-fold parasite reduction per cycle by dihydroartemisinin (without any additional effect by piperaquine) results in a 100,000,000-fold reduction in total parasite biomass during the first two cycles.20 At an initial parasite burden of 1011 parasites, this would leave ~1,000 parasites to be eliminated by residual piperaquine concentrations to prevent recrudescent malaria. Piperaquine alone has not been adequately assessed in P. vivax malaria, but if it is similar to chloroquine, it should provide parasite reduction ratios of ~100 to 1,000 per cycle, so most patients should be parasite free 6–8 days post-treatment if piperaquine levels are sufficient to sustain a maximum parasiticidal effect for this time. If the parasite burden is not eliminated completely, then these remaining parasites can multiply and cause a recrudescent infection. However, a high cure rate of the asexual infection is likely in this study as concentrations of piperaquine after the second asexual cycle (i.e., ≥ 4 days) are highly likely to be able to eliminate ~1,000 parasites. In the first relapse of tropical P. vivax malaria (unaffected by drugs and assuming 1–10 schizonts and a subsequent parasite multiplication rate of ~10 per cycle), the hypnozoite-derived hepatic schizonts must liberate 13–17 days after the onset of the primary illness to produce a symptomatic infection at day 21. However, if residual piperaquine concentrations are sufficiently high, they could suppress and eliminate the asexual parasites derived from 10,000 to 100,000 released merozoites and thereby prevent the first relapse completely. If residual piperaquine concentrations are not sufficiently high for complete elimination, they could cause an initial suppression, resulting in a delayed symptomatic first relapse. Only 14% (15 out of 109) of recurrent P. vivax infections occurred before day 39, which suggests that DHA-PQ treatment prevents a large proportion of the first relapses (Figure 4). The majority of infections (64%, 70 out of 109) occurred between day 42 and 56, suggesting that these are mainly delayed second relapses (Figure 4). There will be some contribution from reinfections, but as entomological inoculation rates are probably well below 0.5/person/year for P. vivax in this area, this contribution is likely to be small.

Bottom Line: Piperaquine pharmacokinetics were described well by a three-compartment distribution model.The results suggest that a large proportion of the first relapses were suppressed completely by residual piperaquine concentrations and that recurrences resulted mainly from emergence of the second or third relapse or from reinfection.This suggests a significant reduction in P. vivax morbidity when using dihydroartemisinin-piperaquine compared with other antimalarial drugs with shorter terminal postprophylactic effects.

View Article: PubMed Central - PubMed

Affiliation: 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

ABSTRACT
Dihydroartemisinin-piperaquine is an effective drug in the treatment of Plasmodium falciparum and P. vivax malaria. The objective of this study was to evaluate the population pharmacokinetics and pharmacodynamics of piperaquine in patients with P. vivax malaria in Thailand after a standard regimen of dihydroartemisinin-piperaquine to determine whether residual piperaquine prevents or delays the emergence of P. vivax relapse. Sparse blood samples were collected from 116 patients. Piperaquine pharmacokinetics were described well by a three-compartment distribution model. Relapsing P. vivax malaria was accommodated by a constant baseline hazard (8.94 relapses/year) with the addition of a surge function in a fixed 3-week interval and a protective piperaquine effect. The results suggest that a large proportion of the first relapses were suppressed completely by residual piperaquine concentrations and that recurrences resulted mainly from emergence of the second or third relapse or from reinfection. This suggests a significant reduction in P. vivax morbidity when using dihydroartemisinin-piperaquine compared with other antimalarial drugs with shorter terminal postprophylactic effects.

No MeSH data available.


Related in: MedlinePlus