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. 2024 Jan 3;79(1):96-99.
doi: 10.1093/jac/dkad352.

Sarecycline pharmacokinetics/pharmacodynamics in the hollow-fibre model of Mycobacterium avium complex: so near and yet so far

Sanjay Singh  1 , Gunavanthi D Boorgula  1 , Santosh Aryal  2 , Julie V Philley  3 , Tawanda Gumbo  4   5 , Shashikant Srivastava  1   6
Affiliations

Sarecycline pharmacokinetics/pharmacodynamics in the hollow-fibre model of Mycobacterium avium complex: so near and yet so far

Sanjay Singh et al. J Antimicrob Chemother. .

Abstract

Background: Poor sustained sputum culture conversion rates with the standard-of-care therapy highlight the need for better drugs to treat Mycobacterium avium complex pulmonary disease (MAC-PD).

Objective: To determine the pharmacokinetics/pharmacodynamics (PK/PD)-optimized exposure of sarecycline and its potential role in treating MAC-PD.

Methods: We performed MIC studies with MAC ATCC 700898 and 19 clinical isolates and test-tube static concentration-response studies. A dynamic hollow-fibre system model of intracellular MAC (HFS-MAC) study was performed mimicking six human-equivalent sarecycline dose concentration-time profiles to identify the PK/PD optimal exposure of sarecycline for MAC kill. The inhibitory sigmoid maximal effect (Emax) model was used for PK/PD analysis.

Results: The sarecycline MIC of MAC ATCC 700898 was 1 mg/L, while the MIC for the 19 clinical strains ranged between 32 and >256 mg/L. The concentration mediating 50% of Emax (EC50) was similar between intracellular and extracellular MAC. In the HFS-MAC, all six sarecycline doses killed intracellular MAC, with an Emax of 1.0 log10 cfu/mL below Day 0 burden (stasis). The sarecycline EC80 (optimal) exposure was identified as AUC0-24/MIC = 139.46.

Conclusions: Sarecycline demonstrated anti-MAC Emax in the HFS-MAC model better than ethambutol but worse than omadacycline (>5 log10 cfu/mL below stasis) in HFS-MAC. However, since currently approved highest oral sarecycline dose achieves an AUC0-24 of 48.2 mg·h/L and MAC MICs are >32 mg/L, the target AUC0-24/MIC of 139.46 is unlikely to be achieved in patients.

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Figures

Figure 1.
Figure 1.
Sarecycline kill curves and dose–response in the HFS-MAC. (a) Time–kill curve of intracellular MAC with different sarecycline exposures. AUC0–24/MIC of 285.39 kept the bacterial burden similar to stasis (Day 0) throughout the 21 day study. (b) Inhibitory sigmoid maximal effect model fit showing the relationship between the intracellular MAC burden and sarecycline exposures in the HFS-MAC. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
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