**6. Conclusion**

*Malaria*

development of artemisinin resistance is of vital importance given the crucial role artemisinin derivatives play in malaria control and treatment programs. Artesunate resistance has already emerged in western Cambodia [1, 63]; however, ACTs are still capable of achieving cure rates exceeding 90%. Since 2001, WHO guidelines have recommended the use of ACTs to include DP, AL, AS-MQ , AS-AQ , and AS-SP to treat patients with uncomplicated *P. falciparum* malaria. Among those ACTs, DP represents a new and extremely promising fixed-dose combination. Several clinical trials have repeatedly shown that DP is a safe and highly efficacious therapy against uncomplicated *P. falciparum* and the asexual stages of *P. vivax* malaria. The risk of recurrent infections was significantly lower for DP, followed by AS-AQ and then AL, supporting the recent WHO recommendation to consider DP as a valid option

These therapies include one artemisinin derivative plus a partner compound, slow-acting, antimalarial drug with a longer half-life [51, 52]. The cumulative risk of parasitological failure was greater in studies of patients treated with AL, AS-MQ , and AS-SP than in patients treated with DP, reflecting the very long half-life of piperaquine. The long half-life of piperaquine is expected to have a major impact in improving the health-care systems of countries in *P. falciparum* malaria endemic areas (**Table 2**). Piperaquine has a large apparent volume of distribution (greater than 500 l/kg) and a terminal elimination half-life estimated around 5 weeks. With increasing sensitivity of assay techniques, the true terminal half-life is probably similar to that of chloroquine, 1–2 months. The oral bioavailability of piperaquine

In addition, the superior efficacy of DP for the treatment of *P. vivax* in malaria endemic areas versus chloroquine or other ACTs may reflect some measures of chloroquine resistance in areas where trials were conducted or comparison with one of the longer acting ACTs. Of the ACTs, DP has the longest half-life and as such was shown to be highly efficacious at preventing *P. vivax* relapses for up to 56 days following treatment. In a separate study, AS-MQ also provided protection against *P. vivax* parasitemia for up to 63 days. The shorter half-life combinations such as AL, although equally effective at rapidly reducing parasite biomass, were shown to provide comparatively little protection against early relapse [64–67]. Accordingly, the DP combination demonstrably has superior PK/PD qualities compared to all

> **Half-life of partner drug per full adult course (US\$)**

4–5 days 14–21 days 9–18 days ~5 weeks 16 days 1–2 months ~4 days (S) or ~8 days (P)

**Regions currently in use purchase cost per course (US\$)**

Africa and EM Africa, SE Asia

EM and WP)

NA

Africa, EM, SE Asia, WP and SA Africa, SE Asia, WP and SA

Africa, EM, SE Asia, WP and SA Africa, EM (IPT in Africa,

for the treatment of uncomplicated *P. falciparum* malaria [64].

increases with coadministration with fat [58, 64–67].

other ACTs recommended by WHO.

Artemether-lumefantrine Artesunate-mefloquine Artesunate-amodiaquine\* Dihydroartemisininpiperaquine

Artesunate-pyronaridine

Sulfadoxine-pyrimethamine

*Asia; t1/2, half-life; WP, Western Pacific.*

Chloroquine1

**Antimalarials Half-life of** 

**artemisinin derivative**

*This refers to the t1/2 of the active metabolite monodesethylamodiaquine; the t1/2 of amodiaquine is ~3 h*

*These former first-line antimalarials are included as a reference. EM, eastern Mediterranean; IPT, intermittent preventive treatment; NA, not applicable; P, pyrimethamine; S, sulfadoxine; SA, South America; SE Asia, Southeast* 

*Plasma half-lives of the partner drugs used in artemisinin-based combination therapies (ACTs) [58, 64–67].*

~3 h <1 h <1 h 45 min <1 h NA NA

**82**

*\**

*1*

**Table 2.**

Artemisinins have been used clinically in the treatment of malaria for over 40 years, during which time their mechanism of action and pharmacokinetic properties have been elucidated. Empirical judgments concerning efficacy and optimal administration have been influenced by their impressive parasite clearance kinetics, which are superior to many commonly used alternatives. Among the five artemisinins in current use, the PK/PD profiles of AS are the best.

This report has also discussed the fact that the rapid efficacy of artemisinins is principally driven by peak concentration (Cmax) from the first drug exposure. Other factors in the pharmacokinetic parameters, such as drug exposure level (AUC) and drug exposure time (half-life), appear to be of lesser importance. By the fundamental and reliable measures of efficacy in cure and mortality rates for uncomplicated and severe malaria, it is demonstrated that current artemisinins (AS, AM, and DHA), performing in roles as ACT or monotherapy, provide a clear-cut advantage over other antimalarials in some geographical locations. The most recent advances in the decrease of the mortality (34.7%) were shown with the use of IV-AS, as compared to IV quinine.

Although the artemisinins are poorly efficacious at achieving 100% cure in malaria when used as monotherapies, this shortage has been overcome using oral ACTs and IV-AS sequentially with a slower acting partner drug such as mefloquine or piperaquine. Previous arguments for the long-term benefits of combination and sequential therapies for preventing resistance and recrudescence still stand. The rapid action and subsequent decrease in mortality show that the artemisinins have a great advantage over other antimalarials when used as ACTs for uncomplicated malaria and in sequential therapy with AS injection in cases of severe and complicated malaria.

As a result of the long half-life of oral piperaquine, DP has excellent PK/PD potential when compared to all other ACTs. Importantly, WHO guidelines for the treatment of malaria expanded to include DP as an ACT option for the "first-line treatment of uncomplicated *P. falciparum* malaria worldwide" [53]. This was categorized as a "Strong Recommendation" and was added due to "High Quality Evidence."

#### **Acknowledgements**

This study was supported by the United States Army Research and Materiel Command. The opinions or assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense.

### **Abbreviations**


*Malaria*
