Dose reduction potential of nanoparticle ARV formulations confirmed in humans


Polly Clayden, HIV i-Base

First in-human trial results of nanoformulations of efavirenz and lopinavir confirmed the potential for a 50% dose reduction to the current standard oral dose of both antiretrovirals.

Andrew Owen presented these findings at CROI 2017 on behalf of colleagues from the University of Liverpool, St Stephens AIDS Trust, Chelsea and Westminster Hospital, London, Clinton Health Access Initiative, Boston, and the Medicines Patent Pool, Geneva.

Professor Owen explained that the group’s solid drug nanoparticle (SDN) formulations of efavirenz (EFV) and lopinavir (LPV) have previously shown preclinical potential for dose reduction while maintaining pharmacokinetics (PK).

The aims of the human study were to: investigate the PK of the EFV and LPV SDN formulations in HIV negative participants; construct population PK models to describe the available data and compare PK to historical data from the originator products; and investigate multiple dosing and safety of the two SDN formulations.

The SDN formulations were powder filled capsules.

The investigators obtained consent from and screened five participants who then received 200mg nano-LPV (boosted with 100 mg originator ritonavir [RTV]) twice daily for seven days. A 12-hour PK profile was generated after the first dose, followed by steady-state PK after the last dose with 56-hour decay. A single plasma concentration was measured on day 3. Participants were assessed for safety at screening, day 1 (before morning and afternoon dose and 4 hours after afternoon dose), day 7, and at completion.

Four participants received 50mg nano-EFV once daily over 21 days (“to err on the side of caution”). A 72-hour PK profile was generated after the first dose, followed by steady-state PK profile after the final dose with 228-hour decay. Single plasma concentrations were measured on days 7, 14, and 17. Safety assessments (including physical examination with vital signs, ECG, urinalysis, laboratory testing) were made at screening, day 1, 2, 14, 21 and at completion.

Professor Owen reported that both SDNs were well tolerated at the studied doses, with no grade 3-4 adverse events.

The investigators used population PK models to analyse PK (one compartment model for LPV and two compartment for EFV), and the resulting models to simulate 1000 HIV negative participants dosed at 200/100 and 300/100 mg LPV/r twice daily, and 200 and 300 mg EFV once daily. These results were compared with simulated 400/100 mg twice-daily originator LPV/r and 600 mg or 400 mg once daily originator EFV.

The simulations predicted that 200mg nano-LPV twice daily (with 100mg originator RTV) would be bioequivalent to twice-daily originator LPV for AUC0-12, Cmax, and C12. See Table 1.

For nano-EFV, the simulations predicted that 300mg once daily would provide bioequivalence to 600mg once daily originator EFV for AUC0-24, Cmax and C12. For C24 bioequivalence not achieved because concentrations were predicted to be higher than those for originator EFV. Simulations were also made for 200mg nano-EFV vs 400mg originator EFV. See Table 1.

Dr Owen noted that there was an indication of an extended tail for both SDN formulations compared to originator formulations.

Table 1: Simulated comparisons of SDN and originator formulations of LPV and EFV
Drug/PK parameter Geometric mean Geometric mean ratio
Lopinavir LPV SDN 200 mg LPV originator 400 mg twice daily GMR (90% CI)
C12 (mg/L) 4.16 4.02 1.04 (0.99-1.08)
AUC0-12 (mg.h/L) 72.35 79.07 0.92 (0.89-0.94)
Cmax (mg/L) 10.69 9.97 1.07 (1.05-1.10)
Efavirenz EFV SDN 300 or 200 mg EFV originator 600 or 400 mg once daily GMR (90% CI)
AUC0-24 (mg.h/L) 51.56 58.61 0.88


C12 (mg/L) 2.03 2.51 0.81 (0.78-0.83)
C24 (mg/L) 1.90 1.44 1.32 (1.26-1.37)
Cmax (mg/L) 2.99 3.36 0.89 (0.87-0.91)

He explained that limitations to the study were small sample size, use of historical data rather than direct comparison with conventional formulations (stage 2 is ongoing), and dose prediction above studied doses assumes linear PK across adult doses.

Dr Owen concluded that these data confirm the potential for 50% dose reductions using a novel approach to formation of LPV and EFV SDNs. If confirmed in larger studies, this approach has the potential for estimated savings of up to US $243 million a year while also freeing up significant manufacturing capacity up to 930 tons a year.

He added that more formulation development is needed for future clinical translation: co-formulation, tableting, stability etc. And that this approach has wide applicability for drugs from various classes for numerous indications.


This group are currently working on a number of other antiretroviral development programmes for oral and long-acting SDN formulations: darunavir, atazanavir, ritonavir and dolutegravir.

If 400 mg EFV becomes the recommended dose SDN formulations can be targeted accordingly. The same applies to lower dose darunavir, if these dose reduction studies are successful.

There also might be benefits with SDN formulations for paediatric ART (particularly for infants and young children) as nanoparticles can be dispersed in water, which might mitigate the need for organic solvents.


Owen A et al. Human confirmation of oral dose reduction potential of nanoparticle ARV formulations. CROI 2017. Oral abstract 39. (Abstract) (Webcast)

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