Abstract
Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twice-daily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrug-resistant tuberculosis (MDR-TB), using a pharmacodynamic target (PDT) that achieves 80% of maximum efficacy. First, in the mouse model of chronic TB, the PK/PD index for delamanid efficacy was determined to be area under the drug concentration-time curve over 24 h divided by MIC (AUC0-24/MIC), with a PDT of 252. Second, in the hollow-fiber system model of tuberculosis, plasma-equivalent PDTs were identified as an AUC0-24/MIC of 195 in log-phase bacteria and 201 in pH 5.8 cultures. Third, delamanid plasma AUC0-24/MIC and sputum bacterial decline data from two early bactericidal activity trials identified a clinical PDT of AUC0-24/MIC of 171. Finally, the CFRs for the currently approved 100-mg BID dose were determined to be above 95% in two MDR-TB clinical trials. The CFR for the 200-mg QD dose, evaluated in a trial in which delamanid was administered as 100 mg BID for 8 weeks plus 200 mg QD for 18 weeks, was 89.3% based on the mouse PDT and >90% on the other PDTs. QTcF (QTc interval corrected for heart rate by Fridericia's formula) prolongation was approximately 50% lower for the 200 mg QD dose than the 100 mg BID dose. In conclusion, while CFRs of 100 mg BID and 200 mg QD delamanid were close to or above 90% in patients with MDR-TB, more-convenient once-daily dosing of delamanid is feasible and likely to have less effect on QTcF prolongation.
Highlights
Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twicedaily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrugresistant tuberculosis (MDR-TB), using a pharmacodynamic target (PDT) that achieves 80% of maximum efficacy
The present study was designed to determine the cumulative fraction of responses (CFRs) for 100 mg delamanid BID and 200 mg delamanid QD to compare the optimality of these two dosing regimens, thereby addressing the feasibility of once-daily administration of delamanid
100 mg BID and 200 mg BID demonstrated similar proportions of sputum culture conversion after 8 weeks of treatment when added to an optimized background regimen (OBR) in pulmonary MDR-TB patients [5]
Summary
Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twicedaily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrugresistant tuberculosis (MDR-TB), using a pharmacodynamic target (PDT) that achieves 80% of maximum efficacy. The CFRs for the currently approved 100-mg BID dose were determined to be above 95% in two MDR-TB clinical trials. A treatment regimen consisting of once-daily delamanid plus OBR has not been examined in isolation in clinical trials, but patients in trial 213 did receive 18 weeks of 200-mg once-daily (QD) dosing after 8 weeks of prior treatment with delamanid 100 mg delamanid twice a day (BID) (Table S5) [6]. The present study was designed to determine the cumulative fraction of responses (CFRs) for 100 mg delamanid BID and 200 mg delamanid QD to compare the optimality of these two dosing regimens, thereby addressing the feasibility of once-daily administration of delamanid. Given the complexity of treatment regimens for MDR-TB, reducing the frequency of dosing via a once-daily regimen could have significant benefits for patient compliance, which in turn would be expected to improve outcomes for this difficult-to-treat infection
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