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.