Additional file 2: of Low heritability in pharmacokinetics of talinolol: a pharmacogenetic twin study on the heritability of the pharmacokinetics of talinolol, a putative probe drug of MDR1 and other membrane transporters

Influence of OCT1 and OATP1B1 on talinolol clearance. (DOCX 15 kb

Kaplan–Meier plot for time to 99% parasite clearance in the per-protocol population.

<p>Time to 99% parasite clearance under parenteral ARS treatment is shown. Using the 10% delta at 24 h, both three-dose regimens are non-inferior to the five-dose regimen in a Cox proportional hazards model. The PP population has been used for the secondary endpoints.</p

Association between delayed anemia and increased white blood cell count at day 7.

<p>Individual white cell counts (WBC) on day 7 (D7) are presented as medians and interquartile ranges, divided into those who developed delayed anemia (12.8 × 10³/μl, interquartile range 9.6–17, <i>n</i> = 186) and those who did not (10.1 × 10³/μl, interquartile range 8.1–12.4, <i>n</i> = 689). Patients with delayed anemia had a significantly higher white blood cell count at day 7 (<i>p <</i> 0.001).</p

Post hoc analyses of patients with anemia.

<p>The right hand side of the diagram (in red) shows patients included in the substudy.</p

Kaplan–Meier plot for time to 90% parasite clearance in the per-protocol population.

<p>Time to 90% parasite clearance under parenteral ARS treatment is shown. Using the 10% delta at 24 h, both three-dose regimens are non-inferior to the five-dose regimen in a Cox proportional hazards model. The PP population has been used for the secondary endpoints.</p

Per-protocol population primary endpoint analysis.

<p>PP treatment difference in proportions of patients with ≥99% parasite reduction, with corresponding 95% confidence intervals. The vertical line indicates the non-inferiority margin (δ). The three-dose i.m. treatment group is non-inferior to the five-dose i.m. treatment group (<i>p =</i> 0.02), whereas the three-dose i.v. group is not non-inferior (<i>p =</i> 0.24). Note that the <i>p</i>-value is calculated using Fisher’s exact test for one-sided equivalence under the assumption that both regimens are equally efficacious.</p

Intention-to-treat population primary endpoint analysis.

<p>ITT treatment difference in proportions of patients with ≥99% parasite reduction, with corresponding 95% confidence intervals. The vertical line indicates the non-inferiority margin (δ). The three-dose i.m. treatment group is non-inferior to the five-dose i.m. treatment group (<i>p =</i> 0.02), whereas the three-dose i.v. group is not non-inferior (<i>p =</i> 0.24). Note that the <i>p</i>-value is calculated using Fisher’s exact test for one-sided equivalence under the assumption that both regimens are equally efficacious.</p

Population pharmacokinetic profiles of artesunate, dihydroartemisinin, and dihydroartemisinin glucuronide.

<p>Plots of observed concentration–time profiles for ARS and its major metabolites, DHA and DHAG, are presented according to treatment regimen. Estimated population mean PK profiles are shown by red lines. The three columns of results for each regimen represent the findings after each dose.</p

Trial profile.

<p>*These patients completed the study but were not included for the primary endpoint analysis because of protocol deviations. ^$These patients completed the study but were not included for the primary endpoint analysis because of sampling issues. ⁺These patients completed the study but were not included for the primary endpoint analysis because of dosing issues. ^§Lost to follow-up includes patients who (i) withdrew consent (<i>n =</i> 8), (ii) moved from the study area (<i>n =</i> 9), and (iii) were discharged from the study due to malaria infection on day 28 (<i>n =</i> 1), amongst a variety of other reasons.</p