Model-based effect evaluation of a novel Mmpl3 inhibitor in C3HeB/FeJ compared to BALB/c mouse models and translation to humans

• Background and Purpose: During tuberculosis drug development, the design of early clinical studies is informed by preclinical animal models. The aim of this work was to describe the exposure-response relationship of a novel inhibitor of mycobacterial MmpL3, prodrug MPL-447, in C3HeB/FeJ mice with non-necrotic or necrotic lesions, and to compare to chronic BALB/c mice information.Experimental Approach: C3HeB/FeJ mice were randomised to placebo and three treatment groups (25, 50 or 100 mg/kg MPL-447). Colony forming unit (CFU) were obtained until week 8 post-treatment. Semi-mechanistic modelling was used to describe growth and killing in relation to exposure. Early bactericidal activity after 14 days (EBA0-14) in humans was predicted using the final model, translational factors and allometric scaling of pharmacokinetics to humans and compared to chronic BALB/c.Key Results: The final model showed 1100% growth and 42% killing of the fast-multiplying bacteria in C3HeB/FeJ mice with necrotic lesions compared to those with non-necrotic lesions. Simulations revealed similar log10CFU reduction on day 14 in C3HeB/FeJ mice with non-necrotic lesions as in chronic BALB/c mice in response to treatment, but 1.7-fold lower reduction in C3HeB/FeJ mice with necrotic lesions. Similar human EBA0-14 was predicted irrespective of the mouse model used. Conclusion and Implications:  The difference in killing of fast-multiplying bacteria in C3HeB/FeJ mice with necrotic lesions compared to C3HeB/FeJ mice without or chronic BALB/C mice was not translated to human early clinical predictions, most likely due to low abundance of these bacteria in humans.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)

Keyword

BALB/c

C3HeB/FeJ

MmpL3 inhibitor

modelling

tuberculosis

translation

Farmaceutisk vetenskap

Pharmaceutical Science

Farmakokinetik och läkemedelsterapi

Pharmacokinetics and Drug Therapy

Publication and Content Type

vet (subject category)

ovr (subject category)