Clinical Pharmacokinetics of the Antimalarial Artemisinin Based on Saliva Sampling

Artemisinin is the parent compound of a novel family of antimalarials. Repetitive administrations of artemisinin to both healthy volunteers and malaria patients have been shown to result in decreased plasma concentrations of the compound, most probably due to an autoinduction of different CYP450 enzymes. The aim of this thesis was to investigate the clinical pharmacokinetics and efficacy of different dosage regimens of the drug, and study the kinetics of the enzyme induction. Moreover, the putative interaction of the compound with blood components was investigated in vitro. Artemisinin was found to distribute into red blood cells, competing with oxygen for binding to hemoglobin. The compound was stable in plasma and, in contrast to previous reports, did not bind to red blood cell membranes. To circumvent the logistical and ethical problems associated with plasma sampling, suitability of saliva as substitute was investigated. Moreover, due to the large number of collected samples, an HPLC method, enabling a direct injection of saliva and plasma samples, was developed. Saliva artemisinin concentrations were found to correlate with its unbound plasma levels, making saliva a suitable body fluid for pharmacokinetic studies of the compound. Based on saliva samples, artemisinin was shown to exhibit a dose-dependent kinetics and efficacy in malaria patients, with a possible sex-effect on the metabolism of the compound during the first treatment day. Moreover, the time-dependent kinetics of the compound was observed in both malaria patients and healthy subjects. A physiological approach was utilized to model the autoinduction in the latter group. A model with a feedback mechanism of enzymes was able to describe the data, with estimations of the half-lives of induction (3.15 hrs) and elimination of enzymes (32.9 hrs), as well as pharmacokinetic parameters of artemisinin. In conclusion, artemisinin was found to exhibit a fast induction of enzymes, with time- and dose-dependent drug kinetics and dose-dependent antimalarial efficacy

Simple Solution to a Common Statistical Problem: Interpreting Multiple Tests

Background: The misinterpretation of the results of multiple statistical tests is an error commonly made in scientific literature. When testing several outcome variables simultaneously, many researchers declare a statistically significant result for each test having a P value of \u3c0.05, for example. This approach ignores the fact that, based on a probability result called the Bonferroni inequality, the risk of incorrectly declaring as significant ≥1 test result increases with the number of tests conducted. The implication of this practice is that many scientific results are presented as statistically significant when the underlying data do not adequately support such a claim (sometimes referred to as false-positive results). Although the sequentially rejective Bonferroni test is well known among statisticians, it is not used routinely in scientific literature. Objective: The intent of this article was to increase the awareness and understanding of the sequentially rejective Bonferroni test, thereby expanding its use. Methods: This article describes the statistical problem and demonstrates how the use of the sequentially rejective Bonferroni test ensures that incorrect declarations of statistical significance for ≥1 test result are bounded by 0.05, for example. Conclusion: The sequentially rejective Bonferroni test is an easily applied, versatile statistical tool that enables researchers to make simultaneous inferences from their data without risking an unacceptably high overall type I error rate

Simple Solution to a Common Statistical Problem: Interpreting Multiple Tests

Background: The misinterpretation of the results of multiple statistical tests is an error commonly made in scientific literature. When testing several outcome variables simultaneously, many researchers declare a statistically significant result for each test having a P value of \u3c0.05, for example. This approach ignores the fact that, based on a probability result called the Bonferroni inequality, the risk of incorrectly declaring as significant ≥1 test result increases with the number of tests conducted. The implication of this practice is that many scientific results are presented as statistically significant when the underlying data do not adequately support such a claim (sometimes referred to as false-positive results). Although the sequentially rejective Bonferroni test is well known among statisticians, it is not used routinely in scientific literature. Objective: The intent of this article was to increase the awareness and understanding of the sequentially rejective Bonferroni test, thereby expanding its use. Methods: This article describes the statistical problem and demonstrates how the use of the sequentially rejective Bonferroni test ensures that incorrect declarations of statistical significance for ≥1 test result are bounded by 0.05, for example. Conclusion: The sequentially rejective Bonferroni test is an easily applied, versatile statistical tool that enables researchers to make simultaneous inferences from their data without risking an unacceptably high overall type I error rate

Simple Solution to a Common Statistical Problem: Interpreting Multiple Tests

Background: The misinterpretation of the results of multiple statistical tests is an error commonly made in scientific literature. When testing several outcome variables simultaneously, many researchers declare a statistically significant result for each test having a P value of \u3c0.05, for example. This approach ignores the fact that, based on a probability result called the Bonferroni inequality, the risk of incorrectly declaring as significant ≥1 test result increases with the number of tests conducted. The implication of this practice is that many scientific results are presented as statistically significant when the underlying data do not adequately support such a claim (sometimes referred to as false-positive results). Although the sequentially rejective Bonferroni test is well known among statisticians, it is not used routinely in scientific literature. Objective: The intent of this article was to increase the awareness and understanding of the sequentially rejective Bonferroni test, thereby expanding its use. Methods: This article describes the statistical problem and demonstrates how the use of the sequentially rejective Bonferroni test ensures that incorrect declarations of statistical significance for ≥1 test result are bounded by 0.05, for example. Conclusion: The sequentially rejective Bonferroni test is an easily applied, versatile statistical tool that enables researchers to make simultaneous inferences from their data without risking an unacceptably high overall type I error rate

Artemisinin Pharmacokinetics and Efficacy in Uncomplicated-Malaria Patients Treated with Two Different Dosage Regimens

The immediate efficacies of two oral dosage regimens of artemisinin were investigated in 77 male and female adult Vietnamese falciparum malaria patients randomly assigned to treatment with either 500 mg of artemisinin daily for 5 days (group A; n = 40) or artemisinin at a dose of 100 mg per day for 2 days, with the dose increased to 250 mg per day for 2 consecutive days and with a final dose of 500 mg on the fifth day (group B; n = 37). Parasitemia was monitored every 4 h. The average parasite clearance time was longer in group B than in group A (means ± standard deviations, 50 ± 23 and 34 ± 14 h, respectively; P < 0.01). Artemisinin concentrations in saliva samples obtained on days 1 and 5 were quantified by high-performance liquid chromatography. The average oral clearance, based on saliva drug concentrations in group B patients, was twofold higher than that in group A patients on day 1 (P < 0.01), with no differences in drug half-lives (P = 0.40), indicating a saturable first-pass metabolism. Female patients had higher oral clearance values on day 1. Artemisinin's pharmacokinetic parameters were similar on day 5 in both groups, although a significant increase in oral clearance from day 1 to day 5 was evident. Thus, artemisinin exhibited both dose- and time-dependent pharmacokinetics. The escalating dose studied did not result in higher artemisinin concentrations toward the end of the treatment period