Early data for rilpivirine long acting formulation supports further investigation for PrEP
Polly Clayden, HIV i-Base
There has been considerable interest in the possibility of long acting formulations of antiretroviral drugs.
Researchers from St Stephen’s AIDS Trust, London and the University of Liverpool have begun investigating the pharmacokinetics (PK) of a novel long acting formulation of rilpivirine (RPV-LA) in development at Jansen Pharmaceuticals. 
RPV-LA is a parenteral formulation – a nanosuspension with 300 mg of the freebase to 1mL of liquid. This formulation makes prolonged plasma exposure possible and has the potential for monthly or less frequent dosing. Akil Jackson presented preliminary results at the 19th CROI from a phase 1 study exploring the PK in plasma, the female genital tract and male rectum over 84 days after a single intramuscular dose of RPV-LA.
The study recruited 27 eligible female healthy volunteers at the St Stephen’s Centre, of which over half were of African or African Caribbean ethnicity. In addition 6 male participants were recruited to the rectum sub-study.
The women received a single intramuscular dose of RPV-LA at doses of either 300, 600, or 1200 mg. Plasma samples were collected on days 0 (pre-dose and 4 and 8 hours), 1, 3, 7, 11, 14, 21, 28, 42, 56, and 84 and genital tract fluid samples were collected at similar times from 8 hours onwards. Biopsies of vaginal epithelium from the peri-cervical fornices were taken at days 14 and (7 or 28) for tissue PK.
The intramuscular dose in the male substudy was 600 mg, with plasma PK samples collected at a similar schedule to the women and rectal biopsies taken at days 7 and 14.
RPV concentrations were quantified using HPLC-MS/MS with a lower limit of 0.25 ng/mL and PK parameters calculated using WinNonLin.
The investigators observed with a dose of 300 mg in women (n=10), there was an early peak in RPV concentrations and gradual elimination over 84 days. RPV concentrations were nearly twice that in cervical vaginal fluid than in plasma: (geometric mean; 90% CI, Cmax ng/mL) 52.4 (44.6 – 6.0) in plasma compared to 102.2 (72.2-132.2) in cervical vaginal fluid. The ratio of cervical vaginal fluid to plasma was (CVF:BP) 1.95 (1.45 – 2.45). Day 24 concentrations were 17.9 (14.0-31.8) in plasma, 29.1 (14.0-31.8) in cervical vaginal fluid and 18.5 (2.2 -34.8) in vaginal tissue; ratio of vaginal tissue to plasma (VT:BP) 1.04 (0.69-1.4).
With a dose of 600 mg (n=10) the genital tract concentrations were more equivalent to those in plasma: 98.4 (81.6-115.2) in plasma and 121 (68.2-174) in cervical vaginal fluid, CVF:BP 1.23 (0.86-1.60). Day 28 concentrations were 54.4 (31.5-107.3) in plasma, 61.6 (11.9-240.8) in cervical vaginal fluid and 59.6 (15.6- 171.4) in vaginal tissue, VT:BP 1.09 (0.29-1.68).
Data for 1200 mg in women (n=7) were incomplete. Results at day 28 were: 85.8 (70.8-101.2) in plasma, 120.8 (103.4-138.2) in cervical vaginal fluid and 61.0 (0.29 – 1.26) in vaginal tissue; VT:BP 0.74 (0.56-0.91).
Dr Jackson noted similar elimination proportionality across the doses. As reference he explained that an oral dose of 25 mg provides peak concentrations of about 200 ng/mL and 150 ng/mL trough.
In men (n=6) maximum plasma concentrations over 84 days with a 600 mg dose of RPV were approximately 30% higher than with the equivalent dose in women and concentrations in rectal fluid were low (possibly due to contamination by fecal fluid). These values were: 131.7 (102.5-160.8) in plasma and 36.4 (18.0 – 54.8) in rectal fluid; ratio of rectal fluid to plasma concentrations (RF: BP) 0.28 (0.19 – 0.3). Although, reassuringly tissue concentrations mirrored that of plasma and on day 14 were 97.7 (67.8-127.6) in plasma, 22.7 (1.3-43.7) in rectal tissue and 87.1 (43.9 – 130.3); ratio of rectal tissue to plasma concentrations (RT:BP) 0.89 (0.65-1.14).
Overall the investigators found all three RPV-LA doses gave prolonged plasma and genital tract exposure. Tissue compartment partitioning showed higher concentrations (at least equivalent or higher) in genital tract fluid than in plasma. Vaginal tissue concentrations were slightly lower than genital tract fluid. Although the reason for this was unclear Dr Jackson suggested it might be due to the non-secretory nature of this mucosa. More data are needed to understand this phenomenon. Male rectum concentrations were equivalent to those observed in plasma.
He concluded that these data support the continued evaluation of RPV-LA for development as a PrEP agent. Next steps include a planned next phase study with multiple intramuscular doses to determine PK and safety and to relate the PK to ex vivo tissue pharmacodynamics to further characterise the dose response of the formulation and inform the use of the agent for this indication.
While this was presented for its potential to reduce the reliance on daily adherence in the context of PrEP, this formulation might have important options for HIV treatment. This would require other ARVs with similar formulations to construct a combination. The lack of negative drug interactions between rilpivirine and dolutegravir (also presented at CROI)  and the development of a similar formulation of GSK-744 (follow on INI to douletegravir) are clearly of interest. 
A safety issue for long-acting formulations, especially in the absence of an antidote to rapidly eliminate the active compound in the event of a severe adverse reaction, might be covered by a period of oral dosing to confirm individual tolerability, especially as both integrase and NNRTI classes have been associated with hypersensitivity reactions.
A recent survey of 400 HIV positive patients attending two US clinics reported 61%, 72% and 84% interest in ART injections based on weekly, two-weekly and monthly formulation respectively, with higher interest in people with concerns about adherence, although 35% were also concerned about needle use. 
- Jackson A et al. Rilpivirine-LA formulation: pharmacokinetics in plasma, genital tract in HIV- females and rectum in males. 19th Conference on Retroviruses and Opportunistic Infections, 5-8 March 2012, Seattle. Oral abstract 35.
- Crauwels H et al. Absence of pharmacokinetic interaction between the NNRTI rilpivirine (TMC278) and the integrase inhibitor raltegravir. Poster abstract 617.
- A study to investigate the safety, tolerability and pharmacokinetics of repeat dose administration of long-acting GSK1265744 and long-acting TMC278 intramuscular and subcutaneous injections in healthy adult subjects.
- Swindells S et al. Long-acting parenteral nanoformulated antiretroviral therapy: patient interest and attitudes. 13th International Workshop on Clinical Pharmacology of HIV Therapy, 16-18 April 2012, Barcelona. Poster abstract P_01. Reviews in Antiviral Therapy & Infectious Diseases – Volume 3: 2012.