Linking In Vitro Intrinsic Dissolution Rate and Thermodynamic Solubility with Pharmacokinetic Profiles of Bedaquiline Long-Acting Aqueous Microsuspensions in Rats

Abstract

Pharmacokinetic (PK) profiles of a range of bedaquiline (BDQ) long-acting injectable (LAI) microsuspensions in rats after parenteral (i.e., intramuscular and subcutaneous) administration were correlated with the in vitro intrinsic dissolution rate (IDR) and thermodynamic solubility of BDQ in media varying in surfactant type and concentration to better understand the impact of different nonionic surfactants on the in vivo performance of BDQ LAI microsuspensions. All LAI formulations had a similar particle size distribution. The investigated surfactants were d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), poloxamer 338, and poloxamer 188. Furthermore, the relevance of medium complexity by using a biorelevant setup to perform in vitro measurements was assessed by comparing IDR and thermodynamic solubility results obtained in biorelevant media and formulation vehicle containing different surfactants in varying concentrations. In the presence of a surfactant, both media could be applied to obtain in vivo representative dissolution and solubility data because the difference between the biorelevant medium and formulation vehicle was predominantly nonsignificant. Therefore, a more simplistic medium in the presence of a surfactant was preferred to obtain in vitro measurements to predict the in vivo PK performance of LAI aqueous suspensions. The type of surfactant influenced the PK profiles of BDQ microsuspensions in rats, which could be the result of a surfactant effect on the IDR and/or thermodynamic solubility of BDQ. Overall, two surfactant groups could be differentiated: TPGS and poloxamers. Most differences between the PK profiles (i.e., maximum concentration observed, time of maximum concentration observed, and area under the curve) were observed during the first 21 days postdose, the time period during which particles in the aqueous suspension are expected to dissolve.

In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in Rats

“…As mentioned above, drug substance precipitation, redissolution, and/or diffusion are likely the driving factors for drug release from the bedaquiline ISGs rather than polymer erosion. The fact that the PK profiles resemble those obtained for 200 mg eq./g bedaquiline microsuspensions administered SC to rats supports this thinking [ 7 ]. The microsuspensions were prepared with crystalline bedaquiline (free form), while X-ray diffraction (XRD), DSC, and IR analysis of spherical ISGs formed from formulations 1 and 2 in 0.05 M phosphate buffer at pH 7.4 or in water confirmed the presence of amorphous bedaquiline free form and/or salt.…”

“…Recent studies have demonstrated favourable pharmacokinetic profiles and antiviral activity after intramuscular or subcutaneous injection of bedaquiline LAI microsuspensions in rodents [ 6 , 7 ]. The high lipophilicity (log P 7.3), low aqueous solubility (<0.005 mg/mL at pH 7.4), and high potency against M. tuberculosis (minimal inhibitory concentration of 0.03 µg/mL) make bedaquiline a suitable candidate for this type of LAI formulation [ 6 , 7 ]. However, LAI microsuspensions have some disadvantages: for example, their complex and costly manufacturing process and physical stability challenges related to particle size growth.…”

Minimal effective dose of bedaquiline administered orally and activity of a long acting formulation of bedaquiline in the murine model of leprosy

“…It has high lipophilicity (logP, 7.3), and a long half-life (about 24 h, functionally or effectively) which makes it suitable for use in an LAI formulation [21]. The efficacy of LAI BDQ has been already demonstrated in a latent tuberculosis infection mouse model [21][22][23]. Due to the very slow doubling time of M. leprae, a unique administration of LAI BDQ could also be considered.…”

Minimal effective dose of oral bedaquiline and activity of a long acting formulation of bedaquiline in the murine model of leprosy Bedaquiline for the treatment of leprosy

“…It has high lipophilicity (logP, 7.3), and a long half-life (about 24 h, functionally or effectively) which makes it suitable for use in an LAI formulation [21]. The efficacy of LAI BDQ has been already demonstrated in a latent tuberculosis infection mouse model [21][22][23]. Due to the very slow doubling time of M. leprae, a unique administration of standard of LAI BDQ could also be considered.…”