Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits

Abstract

SQ109 is a novel well-tolerated drug candidate in clinical development for the treatment of drug resistant tuberculosis (TB). It is the only inhibitor of the MmpL3 mycolic acid transporter in clinical development. No SQ109 resistant mutant has been directly isolated thus far, in vitro, in mice or in patients, tentatively attributed to its multiple targets. It is considered as a potential replacement for poorly tolerated components of multidrug-resistant TB regimens. To prioritize SQ109-containing combinations with best potential for cure and treatment shortening, one must understand its contribution against different bacterial populations in pulmonary lesions. Here we have characterized the pharmacokinetics of SQ109 in the rabbit model of active TB and its penetration at the sites of disease: lung tissue, cellular and necrotic lesions, and caseum. A two-compartment model with first-order absorption and elimination described the plasma pharmacokinetics. At the human-equivalent dose, parameter estimates fell within the ranges published for preclinical species. Tissue concentrations were modelled using an "effect" compartment, showing high accumulation in lung and cellular lesion areas with penetration coefficients in excess of 1,000, and lower passive diffusion in caseum after 7 daily doses. These results, together with the hydrophobic nature and high non-specific caseum binding of SQ109, suggest that multi-week dosing would be required to reach steady state in caseum and poorly vascularized compartments, similar to bedaquiline. Linking lesion pharmacokinetics to SQ109 potency in assays against replicating, non-replicating, and intracellular M. tuberculosis showed SQ109 concentrations markedly above pharmacokinetic-pharmacodynamic targets in lung and cellular lesions throughout the dosing interval. IMPORTANCE Drug-resistant tuberculosis (TB) accounts for over 20% of all fatalities due to drug-resistant pathogens. With recently approved drugs and a promising drug candidate pipeline, the challenge faced by clinical developers is prioritization of drug combinations with the best potential to improve cure rates and shorten treatment duration. To this end, one must understand the contribution of each partner drug against different bacterial populations in pulmonary TB lesions. SQ109 is a safe drug candidate in clinical development for the treatment of multidrug resistant TB. It is active against replicating and non-replicating Mycobacterium tuberculosis persisters in vitro, in mouse models and in patients. SQ109 exhibits extremely low frequency of resistance, unprecedented among all TB drugs so far. Here we characterize the pharmacokinetics and activity of SQ109 at the site of TB disease to inform the selection of drug regimens that account for its lesion-centric pharmacokinetic-pharmacodynamic parameters and best leverage its contribution to efficient disease cure.

Design principles to assemble drug combinations for effective tuberculosis therapy using interpretable pairwise drug response measurements

“… 7 We expanded this 10-drug set (B, clofazimine, E, H, L, M, Pa, Z, P, R) with pairwise measurement to include SQ109 and sutezolid, for a total of 12 drugs ( Table 1 ). A portion of the SQ109 pairwise data was described previously, 14 while its remainder and all the sutezolid data are new to this study. An equipotent mixture of each drug was measured at multiple doses to generate a pairwise dose-response curve.…”

“…M. tuberculosis replicate during incubation in all conditions except dormancy, which induces a metabolically inactive, non-replicative state. 7 , 14 Longitudinal measurements were made, and two time points were targeted that represent a relatively consistent drug exposure time across conditions (constant), as well as the maximal drug exposure time relative to the doubling time of M. tuberculosis in each growth condition (terminal; constant and terminal times were the same for the standard condition, Table 1 ). Five metrics were calculated for each dose-response curve ( Figure 1 B and Table 1 ), capturing combination potency (the normalized area under the dose-response curve up to the 25% growth inhibitory concentration [IC 25 ] [AUC 25 ], effect at infinite drug concentration [maximum achievable effect] [E inf ], normalized growth inhibition effect at infinite drug concentration [maximum achievable effect] [GR inf ]) and drug interactions at low and high doses (fractional inhibitory concentration at 50% growth inhibition [log 2 FIC 50 ], fractional inhibitory concentration at 90% growth inhibition [log 2 FIC 90 ]).…”

“…The pairwise data with sutezolid is new to this study. Some of the SQ109 pairwise measures were reported, 14 and the remaining combination measures in other growth environments are new to this study. All experiments were performed using the same procedures previously described.…”

In Vivo Efficacy of SQ109 against Leishmania donovani, Trypanosoma spp. and Toxoplasma gondii and In Vitro Activity of SQ109 Metabolites

“…SQ109 is an anti-tubercular compound in clinical trials to evaluate efficacy in drugresistant M. tuberculosis-infected patients and a convenient summary of the Russian Phase IIb work was recently reported [27]. As part of a drug repurposing strategy for kinetoplastid diseases, the activity of SQ109 has been evaluated against T. brucei, T. cruzi and Leishmania species in vitro by several research groups, and potent activity was reported against all three parasites [8][9][10][11].…”

Bedaquiline exposure in pregnancy and breastfeeding in women with rifampicin‐resistant tuberculosis

“…The PK of bedaquiline and M2 in breast milk of the mothers with paired plasma and milk samples was characterised using an effect compartment 21 . The effect compartment model described an accumulation ratio (milk:plasma, M:P), and a time delay in the equilibration between the breast milk and plasma concentrations 22,23 . Further information about the effect compartment is provided in the supplementary material.…”