Pharmacokinetics and Pharmacodynamics of Antimalarial Drugs Used in Combination Therapy

Artemisinins are the only currently available mainstream drugs that do not have widespread issues with P. falciparum drug resistance outside of Southeast Asia. Initial reports of artemisinin resistance were noted in western Cambodia near the border with Thailand in 2009 and a possible molecular marker was identified in 2014. For other traditional antimalarial therapies, malaria resistance has been observed to be highly variable and the geographical distribution of resistance and rate of spread have varied significantly. The times for resistance to appear have varied from 278 years for quinine, 35 years for the artemisinins, 12 years for chloroquine, 5 years for mefloquine, 1 year for proguanil, and less than 1 year for sulfadoxine-pyrimethamine and atovaquone. Given the emergence of artemisinin resistance and the possibilities of the spread of resistance out of the border regions of Cambodia, it is essential to prevent the loss of artemisinin combination therapies (ACTs) which are the current first-line treatments for malaria. The use of drugs in combination for treatment of malaria is the best tool to decrease the incidence and spread of malaria drug resistance. The rationale for this approach is threefold: 1) drug combinations are often more effective than monotherapy with one drug; 2) artemisinins substantially reduce gametocyte carriage and thus reduce transmission; and 3) if a mutation arises in a malaria parasite during treatment with one drug, this parasite should still be killed by the partner drug. As each drug protects the other, resistance should be discouraged from occurring. An antimalarial drug combination must provide partners which are each independently capable of treating the disease. In addition, drug combinations used to treat malaria such as the ACTs often provide radical cures of malaria when administered in a 3-day treatment regimen, which also provides protection against emergence of artemisinin resistance.

Drug combination therapy is derived from the premise that administering two or more drugs at the same time that have synergism or additive effects with independent efficacy and different targets will lead to enhanced efficacy and diminished drug resistance. As medicinal chemistry and biological knowledge of the malaria parasite advances, drug combinations for treatment of malaria have become the standard of care. A number of efforts have been made over the years to quantitate the relationship between dose and effect of each drug partner alone and the dose effect relationship of the drugs in combination and to assess whether a drug combination provides a synergistic effect. Antimalarial drug combination therapy (CT) involves the administration of two or more blood schizonticidal drugs each with a separate and different mechanism of action and each targeted to a different parasite protein or process. As described here, drug combinations for antimalarial treatment that include a non-antimalarial drug provided to enhance antimalarial efficacy of a blood schizonticidal drug do not qualify as combination therapy. Artemisinin based combination therapies (ACTs) have been adopted in Asia since 1992 and in Africa since 2000, and these drug combinations have been shown to improve vastly antimalarial treatment efficacy. ACTs are now first-line treatment for P. falciparum malaria globally; they are more effective than non-artemisinins combinations or monotherapies, and ACTs reduce the chances of development of parasite drug resistance. ACTs demonstrate certain key performance parameters associated all of which are related to the unique activities of the artemisinin component, and these features include:1) rapid reduction of the biomass of the parasite; 2) swift clearance of parasites; 3) prompt resolution of patient symptoms; 4) successful treatment against multidrug-resistant P. falciparum and 5) decrease in incidence of gametocyte carriage, which, in theory, will result in turn in reduction of transmission of drug resistant parasites bearing drug resistance alleles.

Combination therapies composed of new antimalarial therapeutics with distinctly different parasite targets and mechanisms of action are the best tools to enhance treatment of uncomplicated falciparum malaria and delay the appearance and expansion of drug resistant malaria. The efficacy of artemisinin combination therapies is the most relevant criteria for evaluating drug combinations. The demonstrated values of an ACT to improve clinical outcomes and delay emergence and spread of parasite drug resistance were all factors in the decision by the WHO to recommend that ACTs be used as the best treatment for treating uncomplicated infections with P. falciparum malaria in Asia and Africa. As discussed in the last chapter, the list of recommended ACTs includes dihydroartemisinin-piperaquine, artemether-lumefantrine, artesunate-mefloquine, artesunate-sulfadoxine-pyrimethamine, and artesunate-amodiaquine. All of these combinations have been shown to be efficacious; however, efficacy of an ACT is affected by resistance to either drug partner. The cost of artemisinin analogues derivatives is a significant contributor to the increased cost of ACT treatment courses. A research project called the artemisinin project was initiated to develop an inexpensive method of semisynthetic production of artemisinins through fermentation rather than deriving artemisinin analogues by extracting artemisinin from the sweet wormwood plant. A cheaper manufacturing method will make ACTs more affordable, and it will be possible to increase distribution to patients in need. Innovations that facilitate production of cheaper ACTs will enhance the odds of a full recovery from falciparum malaria infections with decreased side effects and limit the emergence and spread of drug resistant parasites. Through vigorous efforts to enhance manufacture of inexpensive artemisinins coupled with improved prescription and enhanced patient compliance, the artemisinin drug combinations may still be effective for decades to come.

Most of the antimalarial drugs available on market were introduced in an era prior to the introduction of more modern practices of dose design based on principles of pharmacodynamics (PD) and pharmacokinetics (PK). Antimalarial dose regimens have been derived by empirical means rather than based on PK/PD models to maximize efficacy. These analyses factor in a wide variety of PK/PD parameters to include drug half-life, drug exposure levels, and times, drug metabolism, drug tissue volume of distribution and clearance, and PK inter-individual variations derived from animal model experiments and clinical trials in man. The relationships of drug half-life to antimalarial efficacy and resistance, dosing regimens to antimalarial efficacy and toxicity, and drug peak concentration to rapid antimalarial effects are defined in this chapter. There are significant advantages associated with defining the PK and PD characteristics of novel antimalarial drugs precisely which includes devising better methods of assessing therapeutic response. A clear definition of required PK and PD properties will also help with the design of drug regimens for dosing antimalarial drugs. The dose to be administered, the duration of dosing, and the frequency of dosing, can be modeled to help predict treatment cures and failures. Ultimately, a well-planned dose regimen of an antimalarial combination therapy will aid in slowing the emergence of parasite drug resistance. Antimalarial drugs are administered therapeutically in doses that result in patient blood concentrations far beyond the levels required for maximum effect. To evaluate a usable antimalarial drug, the maximum antimalarial effect observed differs when examining the varied responses between individuals. Thus, defining in vivo therapeutic levels requires analyzing associations between drug levels (PK inputs) and the risk of recurrent parasitemia, recrudescence, and re-infection (PD inputs) which provides important data to both develop and refine antimalarial monotherapy and combination therapies.

Antimalarial drug treatment failures are often not fully investigated, and determining why a patient failed therapy requires not only examining the possibilities of infection with a drug resistant parasite, but also determining drug levels in these patients. Determining drug levels at the point of malaria treatment failure provides useful data even though this is not a routine element of routine patient care or even. Any clinical symptoms or signs at this time should be noted as well given the patient’s illness which in and of itself may affect PK parameters, particularly the volume of distribution. Comparison of PK parameters at the time of late parasitological and clinical failure can be used to assess the impact of illness. In this chapter, the PK/PD parameters of artemisinin compounds will be reviewed. Although the body of literature describing the PK/PD of artemisinin agents is quite limited, the available literature on PK/PD evaluations of artemisinin drugs in man is reviewed in this chapter particularly artemisinin drugs administered in a similar manner as monotherapy. The PK/PD results for administration of artemisinin monotherapy may actually provide greater information than other studies of artemisinin dosage regimens. The PK/PD analysis of artesunate and other artemisinin drugs administered by intravenous, oral, and intramuscular regimens are discussed and derived from combined data with the same drug and dosage regimens. Detailed PK/PD evaluations have demonstrated that artesunate has superior PK/PD behavior among artemisinin derivatives. Among ACT combination drugs, the combination of dihydroartemisinin- piperaquine (DP) has demonstrated superior PK/PD qualities compared to all other ACTs recommended by WHO.

Most of the antimalarial drugs and their combination formulations in current use came on market before the modern use of PK and PD principles for dosage design to maximize drug efficacy. Antimalarial dose regimens have been empirical in nature based on clinical studies with drug half-life, PK inter-individual variation, drug exposure level and time variables have been derived from experimental data or referred to by data from public trials. PK studies involve investigating the relationship between drug absorption, distribution, metabolism, and excretion, while PD studies investigate relationships between the drug target and the drug itself, the mechanism by which the drug works, and the clinical effect the drug provides. Both kinds of studies are involved when assessing drug interactions. Many drugs are metabolized into a similar metabolism pathway or shared an identical target that provides an opportunity to match the proper partner drugs for an antimalarial combination. The ideal PK properties of antimalarial drugs have long been deliberated. From a perspective of preventing drug resistance, drug combination partners should have a similar PK profile. The implications of a PD mismatch on ACTs are not clear at present, particularly in regions with high malaria transmission. Current recommended ACTs have repeatedly shown in a variety of clinical studies that the PD match between ACT partner drugs is good, the combinations are efficacious, well-tolerated, and provide protection against new infections. As discussed in other chapters, PK/PD mismatched ACTs have a known risk of encouraging drug resistance to partner drugs where drug resistance has yet to emerge, and drug combinations that are mismatched will not aid in the important public health job of limiting the spread of resistance.

The mass-action law, the equilibrium law, and the absolute reaction rate theory have all had an impact on the mathematical modeling of biological interactions, and these fundamental discoveries are the foundation for PK/PD modeling. These physicochemical approaches are very useful tools to help understand mathematically the interaction of drugs and combinations with biological systems. Theories have been developed that can be applied to understand a variety of biological applications based on these laws. Accordingly, the algorithms for computer- based analysis and simulation based on these principles been created. Modeling and simulation are important elements in decision making by regulatory agencies affecting both industry and the public. PK models exist to assemble all of the data derived from both nonclinical and clinical studies that have been performed in the drug development process, which provides a means to guide future studies with predictive models. Physiologically based PK (PBPK) models differ from classic PK models due to their incorporation of specific tissue compartments associated with exposure, biotransformation, toxicity, and clearance that are all connected through the flow of blood. The objective of PK/PD modeling as applied to antimalarial drug development is to develop and apply models to characterize pharmacokinetic parameters reflecting the concentration of drug over time and the pharmacodynamic relationships, which describe the effect of drugs with respect to drug concentration. PK modeling elements describe the distribution and clearance kinetics of a drug at the macro level. Adding a PD component to this model adds a drug effect element to characterize drug combination in vivo. These models can assist in choosing appropriate combination partner drugs or alternate first-line treatments for treatment of malaria in a given transmission setting, which may be relevant to malaria eradication efforts.

Population PK studies are integral components of clinical trials with many patients, such as a Phase 3 trial, and these studies involve collection of a few blood samples from each trial participant or from a smaller subgroup of participants selected at random. Computer simulation studies are conducted in advance to describe the number of samples that will be collected from participants and the collection time and frequency of blood sample collection. Population PK studies do not require extensive criteria for design compared to other methods, and these studies are readily adaptable to clinical settings. Population PK modeling provides a means to obtain PK data after administration of a drug from a limited amount of data collected from a population of treated participants. Population PK modeling provides a capability in excess of statistical modeling of sparse data, and it is a powerful tool that can be used to investigate variables affecting inter-individual PK parameter variability. PK data derived from populations can be used to derive the most efficacious and safe dosing regimens. The advantages of population PK/PD modeling and simulation for drug combinations include: 1) clinical trial design optimization for efficacy assessment of drug combination partners; 2) population PK/PD model development validation using limited internal data; 3) PK/PD model external validation utilizing data derived from independent studies; and 4) prospective clinical drug evaluation. PK/PD model outputs can be used to optimize specific drug dosing regimens that can be used to develop guidelines for dosing other drugs, either on market or newly developed, with similar drug mechanism of action or disposition. While the need to conduct modeling to describe drug disposition through profiling PK parameters is clearly established as an essential tool, there is also a need for population level modeling, particularly incorporating effect pathways of drug combination.

The safety profiles of CTs and ACTs are a composite of the safety profiles of the partner drugs in combination. Overall, safety concerns of antimalarial combination therapies leading to serious adverse effects are focused on three known problem areas for these drugs: neurotoxicity, embryotoxicity, and cardiotoxicity. While neurotoxicity induced by artemisinin compounds in animal models has been thoroughly described in the literature, the current clinical treatment for ACTs for a 3-day period is likely too short a time for artemisinin drug exposure to induce neurotoxicity in man. Cardiotoxicity induced by antimalarial drugs such as halofantrine has been shown to result in serious adverse events when dosed to certain subpopulations of patients. Other antimalarial drugs of the quinoline class such as chloroquine and piperaquine have been shown to prolong the QT interval of treated patients, which does focus the attention of both medicinal chemists in early drug development and clinicians testing antimalarial drugs in the field. Early assessment of the potential for cardiotoxicity using hERG testing is an essential element in creating a drug that does not have overt potential for cardiotoxicity. While embryotoxicity induced by artemisinin compounds has been noted in various animal models, the period of concern is primarily in the first trimester where ACT administration to pregnant women has been contraindicated. The PK/PD data from pre-clinical studies has been very useful in establishing treatment parameters for artemisinin drugs to avoid potential embryotoxicity in man. A review of the literature on this subject will be provided in this chapter to assess the limitations of CTs and ACTs therapy to avoid triggering serious adverse events associated with neurotoxicity, cardiotoxicity, and embryotoxicity.

Several drug development strategies for novel antimalarial drugs have been created to counter the rise of malaria drug resistance. These strategies include optimizing new antimalarial drug combinations through laboratory testing and clinical development. ACTs are the most successful drug combinations invented to date for treatment of malaria worldwide, however, the growing tide of malaria resistance, particularly in Southeast Asia, provides a compelling need to discover novel chemical entities to combine with artemisinin analogues or create new antimalarial combinations using existing drugs. Strategies to find novel chemical entities are outlined in this section ranging from irrational drug discovery with whole-cell phenotypic screening to target based screening against specific Plasmodium targets. Implementation of antimalarial drug combinations with diverse PK/PD profiles will likely require evaluation of multiple outcomes, which further complicates statistical modelling for factorial designs. Well- constructed, carefully conducted, and statistically rigorous clinical pharmacology studies are necessary for development of new malaria treatments and practical methods must be put in place for post licensure marketing surveillance to detect both emerging drug resistance and adverse effects. While a number of novel chemical entities are under development, bringing new, efficacious, safe, and welltolerated antimalarial drugs to market is a quite a challenge particularly in today’s regulatory environment. In addition, antimalarial treatment currently involves combinations of drugs with synergistic or additive properties, which makes drug discovery and development even more challenging.