Cabotegravir + Rifampin = Prohibited

Study Design

This study was a phase I, open label fixed sequence cross-over study. Fifteen healthy subjects received a single dose of cabotegravir (CAB) 30 mg on day one with PK sampling to day 7. From days 8 to 20, patients also received daily rifampin (RIF) 600 mg. A single dose of CAB 30 mg and a single dose of RIF 600 mg continuing through PK sample collection to day 28.

Study Results

Geometric mean CAB values prior to administration of RIF included the following: AUC 146 mg*h/mL, Cmax 3.61 mg/ml, T ½ 38.6 h, and CL/F 0.21 L/h. Two weeks after initiating once daily dosing of rifampin, the same values were AUC 59.7 mg*h/mL, Cmax 3.39 mg/ml, T ½ 16.4 h, and CL/F 0.5 L/h.

Study Conclusions

References

Ford SL, K Sutton, Y Lou, J Zhang, A Tenorio, C Trezza, et al. Rifampin (rif) decreases cabotegravir (cab) exposure following oral co-administration. 17th International Workshop On Clinical Pharmacology Of Hiv And Hepatitis Therapy. Washington, DC, USA. ; 2016.

Study Design

The physiologically-based pharmacokinetic (PBPK) model was designed in Simbiology v. 4.3.1 (MATLAB 2013b) and 100 healthy adult individuals were used for simulations. Standard oral doses of 30 mg and 600 mg were used for cabotegravir (CAB), and (Rifampin) RIF, respectively. Loading doses of 800 mg were used for CAB. 400 mg/800 mg were used as q4/8-weekly IM maintenance doses for CAB. Models were also qualified against PK data in the LATTE-2 IM CAB study. Oral CAB-RIF, and midazolam (CYP3A4 probe)- RIF drug-drug interaction (DDI) models were also qualified against PK data from clinical studies. The PBPK models were assumed to be qualified if the simulated values were ± 100 % from the mean reported clinical values. The effect of 600 mg oral once-daily RIF on the PK of long acting (LA) IM 4-weekly CAB loading and maintenance doses was evaluated. Variation in PK parameters AUC, Cmax and Ctrough values are reported.

Study Results

For the IM loading dose of CAB with 600 mg OD RIF, the PK parameters Cmax, AUC and Ctrough decreased by 57.6%, 43.8% and 44.0%, respectively, compared to CAB alone. For the maintenance doses there was an overall reduction between 39% and 46% in the PK parameters.

Study Conclusions

Models were qualified and PK data successfully predicted for CAB with RIF. This computational approach supports the prediction of potential DDIs for LA regimens, which cannot be readily investigated in vivo due to ethical and logistical barriers. This approach could rationally guide the design of alternative dosing strategies. The co-administration of RIF with CAB is predicted to substantially decrease cabotegravir concentrations.

References

Rajoli, RKR, Curley, P, Back, D, Flexner, CW, Owen, A, Siccardi, M. In silico drug interaction of long-acting rilpivirine and cabotegravir with rifampin. Conference On Retroviruses And Opportunistic Infections. Boston, MA, USA. ; March 2018.

Study Design

The physiologically-based pharmacokinetic (PBPK) model was designed in Simbiology v. 4.3.1 (MATLAB 2013b) and 100 healthy adult individuals were used for simulations. Standard oral doses of 30 mg and 600 mg were used for cabotegravir (CAB), and (Rifampin) RIF, respectively. Loading doses of 800 mg were used for CAB. 400 mg/800 mg were used as q4/8-weekly IM maintenance doses for CAB. Models were also qualified against PK data in the LATTE-2 IM CAB study. Oral CAB-RIF, and midazolam (CYP3A4 probe)- RIF drug-drug interaction (DDI) models were also qualified against PK data from clinical studies. The PBPK models were assumed to be qualified if the simulated values were ± 100 % from the mean reported clinical values. The effect of 600 mg oral once-daily RIF on the PK of long acting (LA) IM 4-weekly CAB loading and maintenance doses was evaluated. Variation in PK parameters AUC, Cmax and Ctrough values are reported.

Study Results

For the IM loading dose of CAB with 600 mg OD RIF, the PK parameters Cmax, AUC and Ctrough decreased by 57.6%, 43.8% and 44.0%, respectively, compared to CAB alone. For the maintenance doses there was an overall reduction between 39% and 46% in the PK parameters.

Study Conclusions

Models were qualified and PK data successfully predicted for CAB with RIF. This computational approach supports the prediction of potential DDIs for LA regimens, which cannot be readily investigated in vivo due to ethical and logistical barriers. This approach could rationally guide the design of alternative dosing strategies. The co-administration of RIF with CAB is predicted to substantially decrease cabotegravir concentrations.

References

Rajoli, RKR, Curley, P, Back, D, Flexner, CW, Owen, A, Siccardi, M. In silico drug interaction of long-acting rilpivirine and cabotegravir with rifampin. Conference On Retroviruses And Opportunistic Infections. Boston, MA, USA. ; March 2018.

Study Design

This study was a phase I, open label fixed sequence cross-over study. Fifteen healthy subjects received a single dose of cabotegravir (CAB) 30 mg on day one with PK sampling to day 7. From days 8 to 20, patients also received daily rifampin (RIF) 600 mg. A single dose of CAB 30 mg and a single dose of RIF 600 mg continuing through PK sample collection to day 28.

Study Results

Geometric mean CAB values prior to administration of RIF included the following: AUC 146 mg*h/mL, Cmax 3.61 mg/ml, T ½ 38.6 h, and CL/F 0.21 L/h. Two weeks after initiating once daily dosing of rifampin, the same values were AUC 59.7 mg*h/mL, Cmax 3.39 mg/ml, T ½ 16.4 h, and CL/F 0.5 L/h.

Study Conclusions

References

Rajoli, RKR, Curley, P, Back, D, Flexner, CW, Owen, A, Siccardi, M. In silico drug interaction of long-acting rilpivirine and cabotegravir with rifampin. Conference On Retroviruses And Opportunistic Infections. Boston, MA, USA. ; March 2018.