MT-921

Background/Objectives: This study compared fat reduction efficacy of cholic acid-based formulation (MT921) and deoxycholic acid (DCA), as well as skin adverse reactions (ADR), in mini pigs, mice, and rats. DCA is the active pharmaceutical ingredient found in several fat-dissolving injectables, such as Kybella®, V-OLET®, and Bellacholine®. Methods: In one study, single subcutaneous (s.c.) injections of 1.5% MT921 and 1% DCA were administered to the back of a mini pig at different sites and time points to ascertain histopathological events. In another study, three mini pigs received six repeated s.c. injections of 1.5% MT921 and 1% DCA at 4-week intervals, and changes in subcutaneous fat volume were monitored by magnetic resonance imaging (MRI), along with visual examination for ADRs. Additional ADRs were assessed in rodents, such as ulcerative dermatitis (UD) following MT921 and DCA s.c. injections in ICR/CD1 mice, and footpad edema after intraplantar injections in SD rats. Results: In mini pigs, 1.5% MT921 and 1% DCA induced comparable localized fat necrosis, accompanied by inflammatory cell influx and fibrosis. Also, repeated injections of 1.5% MT921 and 1% DCA induced comparable fat volume reduction in outer subcutaneous layer, though changes in middle subcutaneous layer was unaffected. Notably, MT921 evoked milder ADR based on lower incidence of hematoma and absence of nodules in mini pigs, less severe UD in mice, and reduced edema in rats. Conclusions: Local injections of 1.5% MT921 demonstrated fat-reduction efficacy comparable to 1% DCA while eliciting fewer and milder ADRs, supporting MT921 as a promising alternative lipolytic agent.

MT921 is a new injectable drug developed by Medytox Inc. to reduce submental fat. Cholic acid is the active pharmaceutical ingredient, a primary bile acid biosynthesized from cholesterol, endogenously produced by liver in humans and other mammals. Although individuals treated with MT921 could be administered with multiple medications, such as those for hypertension, diabetes, and hyperlipidemia, the pharmacokinetic drug–drug interaction (DDI) has not been investigated yet. Therefore, we studied in vitro against drug-metabolizing enzymes and transporters. Moreover, we predicted the potential DDI between MT921 and drugs for chronic diseases using physiologically-based pharmacokinetic (PBPK) modeling and simulation. The magnitude of DDI was found to be negligible in in vitro inhibition and induction of cytochrome P450s and UDP-glucuronosyltransferases. Organic anion transporting polypeptide (OATP)1B3, organic anion transporter (OAT)3, Na+-taurocholate cotransporting polypeptide (NTCP), and apical sodium-dependent bile acid transporter (ASBT) are mainly involved in MT921 transport. Based on the result of in vitro experiments, the PBPK model of MT921 was developed and evaluated by clinical data. Furthermore, the PBPK model of amlodipine was developed and evaluated. PBPK DDI simulation results indicated that the pharmacokinetics of MT921 was not affected by the perpetrator drugs. In conclusion, MT921 could be administered without a DDI risk based on in vitro study and related in silico simulation. Further clinical studies are needed to validate this finding.