Emulsion-templated spray drying to form solid drug nanoparticle (SDN) formulations of efavirenz (EFV) and lopinavir (LPV) previously showed preclinical potential for dose reduction while maintaining pharmacokinetics (PK). This study sought to confirm this in healthy volunteers after single dose and at steady state.
Healthy volunteers (n=4) were consented and screened before receiving 50mg NANO-EFV OD over 21 days. A 72-hour PK profile was generated after the first dose, followed by steady-state PK profile after the final dose with 228-hour plasma decay. Single plasma concentration measurements were also made on days 7, 14, and 17. Safety (including physical examination with vital signs, ECG, urinalysis, laboratory testing) occurred at screening, day 1, 2, 14, 21 and at completion. Five volunteers were consented and screened before receiving 200mg NANO-LPV (boosted with 100mg Norvir) BID over 7 days. A 12-hour PK profile was generated after the first dose, followed by steady-state PK after the final dose with 56-hour decay. A single plasma concentration measurement was also made on day 3. Safety assessments occurred at screening, day 1 (pre morning and afternoon dose and 4 hours post afternoon dose), day 7, and at completion. PK was analysed through population-PK models, with the resulting models used to simulate (n=1000) bioequivalence with previously published clinical data.
Both nanoformulations proved to be well tolerated at the studied doses, with no grade 3-4 adverse events. For NANO-EFV, simulations predicted 300mg OD would provide bioequivalence to 600mg OD Sustiva for AUC0-24, Cmax, C12, but not C24 (see table). Importantly, bioequivalence was missed at C24 because concentrations were predicted to be higher than those for Sustiva. Similar simulations were made for 200mg NANO-EFV versus 400mg of the conventional formulation. For NANO-LPV, simulations predicted 200mg BID (with 100mg Norvir) would provide bioequivalence to BID Kaletra for AUC0-12, Cmax, and C12.
These data confirm the potential for a 50% dose reduction while maintaining therapeutic exposure, using a novel approach to formation of SDNs. If confirmed in larger future studies, the approach has the potential for savings up to 243 million USD per year while also freeing up manufacturing capacity up to 930 tons per year.