Identification of optimal dose and dosing regimen of clofazimine for the treatment of multi-drug resistant tuberculosis (MDR-TB) based on pharmacokinetic modeling Ganesan S1, Sunkara G2 , McNeeley D3 and Hughes D4 Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, 1Hyderabad, India Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, 2East Hanover, USA Novartis Pharma corporation, 3East Hanover, USA Novartis Pharma AG, 4Basel, Switzerland Introduction Clofazimine (Lamprene®, Novartis) is a lipophilic substituted riminophenazine dye with antimycobacterial and anti-inflammatory properties that was approved in 1969 for the treatment of leprosy1 and for management of inflammatory states such as erythema nodosum leprosum2 Currently clofazimine is classified as a WHO Group 5 (unproven efficacy), second-line drug recommended for the treatment of MDR-TB Clofazimine is highly lipophilic, is absorbed slowly, and accumulates mainly in fatty tissue and in macrophages of the reticuloendothelial system Clofazimine has not demonstrated early bactericidal activity in a recent phase 2a study (Diacon 2015). The anti-mycobacterial activity of clofazimine is presumed to be due to its ability to sterilize TB lesions (Cholo 2012) . Table 1: Population Pharmacokinetic parameter estimates of clofazimine PK parameter Estimate %CV Ka 0.118 45.9 CL 10.7 36.7 V 352 0.0003 Q 42.6 31.6 V2 3960 Proportional error 30.11 Additive error 1.89 Ka- rate constant for first order absorption, CL-clearance, V-volume of central compartment, Q- rate constant for inter-compartmental transfer, V2- volume of peripheral compartment and %CV- Coefficient of Variance Figure 1: Two-compartment population PK model Objective The objective of this research work was to determine the optimal dose and dosing regimen of clofazimine based on its pharmacokinetic properties and to achieve the target concentration during intensive phase to sustain anti-mycobacterial activity Methodology A population pharmacokinetic model for clofazimine was developed by pooling the data from two clinical studies of clofazimine after single and multiple dosing in healthy volunteers (200 mg dose once a day) and leprosy patients (50 or 100 mg once a day), respectively Plasma concentration data from these two studies were analyzed by non-linear mixed effect modelling using a first order conditional estimation method with interaction. Model selection was performed by using the objective function value and visual inspection of diagnostic plots The population estimates in combination with in vitro MIC99 data (1.18 µg/mL) in drug resistant clinical MDR-TB isolates and in vivo data from mouse efficacy model3, were used for performing several simulations. The simulations were used to identify the dose and dose regimen that achieve a target concentration of 1.18 µg/mL in earliest treatment duration (~ 6 weeks) and sustain it for 18 weeks of the intensive phase of TB treatment Observed vs. individual estimate Observed vs. population estimate Figure 2: Scatter plot of PK parameters Results As shown in Figure 1 and 2, the clofazimine plasma concentration time data were best described by a two-compartment model with first order absorption. Inter-individual variability component was included in all parameters. Based on the figure 2, key co-variates such as body weight, age did not have any clear relationship As shown in Figure 3, several clinical scenarios with different dose and dosing durations were simulated during the intensive phase of treatment (upto 24 weeks. The time to reach the target concentration of 1.18 µg/mL, and the duration for which the plasma concentrations are above the anticipated target concentrations were considered as appropriate criteria for the selection of dose and dosing regimen The simulations indicate that the steady-state concentration (Day ~110) of clofazimine after once a day administration of 100 mg is only about 0.84 μg/mL. So the loading dose of 200 mg once daily administration of clofazimine for 18 weeks followed by once daily administration of 100 mg of clofazimine till 24 weeks is selected based on the PK simulations Figure 3: Simulated plasma concentration-time profiles of Clofazimine following repeated oral administration up to 24 weeks Conclusion Based on the population PK analysis, loading dose of 200 mg QD for 18 weeks followed by 100 mg QD of clofazimine till 24 weeks is expected to provide target plasma concentrations of clofazimine for eliciting its anti-microbiological property where inhibitory concentrations can be achieved for the clinical resistant isolates. Treatment duration of >18 months as recommended by WHO treatment guidelines to be followed in the proposed clinical study. Steady-state concentrations are reached at about 110 days. In order to reach steady-state faster, a loading dose of 200 mg once daily is administered for 18 weeks to reach the target plasma concentrations in humans during the initial months of TB treatment. The maintenance dose of 100 mg enables the anti-mycobacterial activity of clofazimine in MDR-TB patients to persist during the continuation phase and beyond the end of treatment course References [Anon (2008)] Clofazimine. Tuberculosis (Edinburgh); 88:96-9. [Dey T, Brigden G, Cox H, et al (2013)] Outcomes of clofazimine for the treatment of drug resistant tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother; 68(2): 284-93. [Xu J, Lu Y, Fu L, et al (2012)] In vitro and in vivo activity of clofazimine against Mycobacterium tuberculosis persisters. Int J Tuberc Lung Dis; 16(8): 1119-25. [Cholo, MC, Steel, HC, Fourie, PB, et al (2012) ]Clofazimine: current status and future prospects. J Antimicrob Chemother; 67(2):290-8. [Diacon A (2015)] Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline. Am J Respir Crit Care Med 191(8), 943–953 Poster presented at the Union World Health Conference on Lung Cancer, 2nd-6th December 2015, Cape Town, South Africa