Pharmacokinetics and Drug-Drug Interactions of Long-Acting Intramuscular Cabotegravir and Rilpivirine

Abstract

Combined antiretroviral treatments have significantly improved the morbidity and mortality related to HIV infection, thus transforming HIV infection into a chronic disease; however, the efficacy of antiretroviral treatments is highly dependent on the ability of infected individuals to adhere to life-long drug combination therapies. A major milestone in HIV treatment is the marketing of the long-acting intramuscular antiretroviral drugs cabotegravir and rilpivirine, allowing for infrequent drug administration, with the potential to improve adherence to therapy and treatment satisfaction. Intramuscular administration of cabotegravir and rilpivirine leads to differences in pharmacokinetics and drug-drug interaction (DDI) profiles compared with oral administration. A notable difference is the long elimination half-life with intramuscular administration, which reaches 5.6-11.5 weeks for cabotegravir and 13-28 weeks for rilpivirine, compared with 41 and 45 h, respectively, with their oral administration. Cabotegravir and rilpivirine have a low potential to cause DDIs, however these drugs can be victims of DDIs. Cabotegravir is mainly metabolized by UGT1A1, and rilpivirine is mainly metabolized by CYP3A4, therefore these agents are susceptible to DDIs with inhibitors, and particularly inducers of drug-metabolizing enzymes. Intramuscular administration of cabotegravir and rilpivirine has the advantage of eliminating DDIs occurring at the gastrointestinal level, however interactions can still occur at the hepatic level. This review provides insight on the intramuscular administration of drugs and summarizes the pharmacology of long-acting cabotegravir and rilpivirine. Particular emphasis is placed on DDI profiles after oral and intramuscular administration of these antiretroviral drugs.

Fig. 1

Mechanisms of drug–drug interaction after oral versus intramuscular administration of cabotegravir and rilpivirine

Fig. 2

a Impact of oral cabotegravir on co-medication pharmacokinetics from drug–drug interaction crossover studies in healthy volunteers. 1. Period 1: Oral midazolam 3 mg daily for 10 days. Period 2: Oral midazolam 3 mg + cabotegravir 30 mg daily for 14 days (n = 12). 2. Period 1: Levonorgestrel/ethinylestradiol 0.15/0.03 mg daily for 10 days. Period 2: Levonorgestrel/ethinylestradiol 0.15/0.03 mg + cabotegravir 30 mg daily for 10 days (n = 20). 3. Period 1: Cabotegravir 30 mg daily for 12 days. Period 2: Rilpivirine 25 mg daily for 12 days. Period 3: Cabotegravir 30 mg + rilpivirine 25 mg daily for 12 days (n = 11). b Impact of co-medications on oral cabotegravir pharmacokinetics from drug–drug interaction crossover studies in healthy volunteers. 1. Period 1: Cabotegravir 30 mg daily for 10 days. Period 2: Cabotegravir 30 mg + etravirine 200 mg daily for 14 days (n = 12) 2. Period 1: Cabotegravir 30 mg daily for 12 days. Period 2: Rilpivirine 30 mg daily for 12 days. Period 3: Cabotegravir 30 mg + rilpivirine 25 mg daily for 12 days (n = 11). 3. Cabotegravir 30 mg single-dose day 1. Rifampicin 600 mg daily days 8–28 with cabotegravir 30 mg single dose on day 21 (n = 15). 4. Period 1: Cabotegravir 30 mg daily for 14 days. Period 2: Cabotegravir 30 mg + rifabutin 300 mg for 14 days (n = 15). Data are expressed as area under the curve (squares) and trough plasma concentration (triangles) geometric mean ratios + 90% confidence intervals for cabotegravir with and without co-medication. The bioequivalence margin (0.8–1.25) is indicated by dashed vertical lines. EE ethinylestradiol, LNG levonorgestrel, sd single dose [34, 70, 71, 85, 86, 94]

Fig. 3

a Impact of oral rilpivirine on co-medication pharmacokinetics from drug–drug interaction crossover studies in healthy volunteers. 1. Period 1: Atorvastatin 40 mg daily for 4 days. Period 2: Rilpivirine 150 mg daily for 15 days + atorvastatin 40 mg daily days 12–15 (n = 16). 2. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Darunavir/ritonavir 800/100 mg daily for 22 days + rilpivirine 150 mg daily day 12–22 (n = 16). 3a. Period 1: Cabotegravir 30 mg daily for 12 days. Period 2: Rilpivirine 25 mg daily for 11 or 12 days. Period 3: Cabotegravir 30 mg daily + rilpivirine 25 mg daily, for 12 days (n = 11). 3b. Period 1: Dolutegravir 50 mg daily for 5 days. Period 2: Rilpivirine 25 mg daily for 11 or 12 days. Period 3: Dolutegravir 50 daily + rilpivirine 25 mg daily for 5 days (n = 16). 4. Period 1: Grazoprevir/elbasvir 200/50 mg daily for 8 days. Period 2: Rilpivirine 25 mg daily for 11 days. Period 3: Grazoprevir/elbasvir 200/50 mg daily + rilpivirine 25 mg daily for 9 days (n = 20). 5. Period 1: Rilpivirine 150 mg daily for 8 days. Period 2: Tenofovir disoproxil fumarate 300 mg daily for 16 days + rilpivirine 150 mg daily either days 1–8 or days 9–16 (n = 15). 6. Period 1: Norethindrone/ethinylestradiol 1/0.035 mg in three 21-day cycles + rilpivirine 25 mg daily on days 1–15 of the third cycle (n = 18). 7. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Ketoconazole 400 mg daily for 22 days + rilpivirine 150 mg daily days 12–22. 8. Period 1: Rilpivirine 150 mg daily for 10 days. Period 2: Lopinavir/ritonavir 400/100 mg twice daily for 20 days + rilpivirine 150 mg days 11–20 (n = 14). 9. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Omeprazole 20 mg daily for 22 days + rilpivirine 150 mg on days 12–22 (n = 16). 10. Period 1: Paracetamol 500 mg, single dose. Period 2: Rilpivirine 150 mg daily for 12 days + paracetamol 500 mg single dose on day 11 (n = 16). 11. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Rifabutin 300 mg daily for 11 days. Period 3: Rilpivirine 150 mg + rifabutin 300 mg daily for 11 days (n = 18). 12. Period 1: Sildenafil 50 mg, single dose. Period 2: Rilpivirine 75 mg daily for 12 days + sildenafil 50 mg single dose on day 12 (n = 16). 13. Period 1: Sofosbuvir/velpatasvir 400/100 mg daily for 8 days. Period 2: Emtricitabine/rilpivirine/tenofovir disoproxil fumarate 200/25/300 mg + sofosbuvir/velpatasvir 400/100 mg daily for 8 days (n = 24). 14. Period 1: Rilpivirine 25 mg daily for 14 days. Period 2: Tenofovir alafenamide fumarate 25 mg daily for 14 days. Period 3: Rilpivirine 25 mg + tenofovir alafenamide fumarate 25 mg daily, for 14 days (n = 17). 15. Stable methadone dose (60–150 mg daily) for 25 days + rilpivirine 25 mg daily on days 15–25 (n = 13). (b) Impact of co-medications on oral rilpivirine pharmacokinetics from drug–drug interaction crossover studies in healthy volunteers. 1. Period 1: Atorvastatin 40 mg daily for 4 days. Period 2: Rilpivirine 150 mg daily for 15 days + atorvastatin 40 mg daily days 12–15 (n = 16). 2. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Darunavir/ritonavir 800/100 mg daily for 22 days + rilpivirine 150 mg daily days 12–22 (n = 16). 3a. Period 1: Cabotegravir 30 mg daily for 12 days. Period 2: Rilpivirine 25 mg daily for 11 or 12 days. Period 3: Cabotegravir 30 mg daily + rilpivirine 25 mg daily for 12 days (n = 11). 3b. Period 1: Dolutegravir 50 mg daily for 5 days. Period 2: Rilpivirine 25 mg daily for 11 or 12 days. Period 3: Dolutegravir 50 daily + rilpivirine 25 mg daily for 5 days (n = 16). 4. Period 1: Grazoprevir/elbasvir 200/50 mg daily for 8 days. Period 2: Rilpivirine 25 mg daily for 11 days. Period 3: Grazoprevir/elbasvir 200/50 mg daily + rilpivirine 25 mg daily for 9 days (n = 20). 5. Period 1: Rilpivirine 150 mg daily for 8 days. Period 2: Tenofovir disoproxil fumarate 300 mg daily for 16 days + rilpivirine 150 mg daily either days 1–8 or days 9–16 (n = 15). 6. Period 1: Rilpivirine 150 mg single dose. Period 2: Rilpivirine 150 mg single dose 2 h after famotidine 40 mg single dose (n = 24). 7. Period 1: Rilpivirine 150 mg daily. Period 2: Ketoconazole 400 mg daily for 22 days + rilpivirine 150 mg daily days 12–22 (n = 14). 8. Period 1: Rilpivirine 150 mg daily for 10 days. Period 2: Lopinavir/ritonavir 400/100 mg twice daily for 20 days + rilpivirine 150 mg days 11–20 (n = 14). 9. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Omeprazole 20 mg daily for 22 days + rilpivirine 150 mg on days 12–22 (n = 16). 10. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Rifabutin 300 mg daily for 11 days. Period 3: Rilpivirine 150 mg + rifabutin 300 mg daily for 11 days (n = 18). 11. Period 1: Rilpivirine 150 mg daily. Period 2: Rilpivirine 150 mg daily + rifampicin 600 mg daily (n = 16). 12. Period 1: Sildenafil 50 mg, single dose. Period 2: rilpivirine 75 mg daily for 12 days + sildenafil 50 mg single dose on day 12 (n = 16). 13. Period 1: Sofosbuvir/velpatasvir 400/100 mg daily for 8 days. Period 2: Emtricitabine/rilpivirine/tenofovir disoproxil fumarate 200/25/300 mg + sofosbuvir/velpatasvir 400/100 mg daily for 8 days (n = 24). Data are presented as area under the curve (squares) and trough plasma concentration (triangles) geometric mean ratios + 90% confidence intervals for rilpivirine with and without co-medication. The bioequivalence margin (0.8–1.25) is indicated by dashed vertical lines. CAB cabotegravir, DRV/RTV darunavir/ritonavir, DTG dolutegravir, GS-331007 metabolite of sofosbuvir, GZR/EBR grazoprevir/elbasvir, LPV/RTV lopinavir/ritonavir, NOR/EE norgestrel/ethinylestradiol, RPV rilpivirine, sd single dose, SOF/VEL sofosbuvir/velpatasvir, TAF tenofovir alafenamide, TDF tenofovir disoproxil fumarate [, –83, 88, 95, 96].

Fig. 3

a Impact of oral rilpivirine on co-medication pharmacokinetics from drug–drug interaction crossover studies in healthy volunteers. 1. Period 1: Atorvastatin 40 mg daily for 4 days. Period 2: Rilpivirine 150 mg daily for 15 days + atorvastatin 40 mg daily days 12–15 (n = 16). 2. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Darunavir/ritonavir 800/100 mg daily for 22 days + rilpivirine 150 mg daily day 12–22 (n = 16). 3a. Period 1: Cabotegravir 30 mg daily for 12 days. Period 2: Rilpivirine 25 mg daily for 11 or 12 days. Period 3: Cabotegravir 30 mg daily + rilpivirine 25 mg daily, for 12 days (n = 11). 3b. Period 1: Dolutegravir 50 mg daily for 5 days. Period 2: Rilpivirine 25 mg daily for 11 or 12 days. Period 3: Dolutegravir 50 daily + rilpivirine 25 mg daily for 5 days (n = 16). 4. Period 1: Grazoprevir/elbasvir 200/50 mg daily for 8 days. Period 2: Rilpivirine 25 mg daily for 11 days. Period 3: Grazoprevir/elbasvir 200/50 mg daily + rilpivirine 25 mg daily for 9 days (n = 20). 5. Period 1: Rilpivirine 150 mg daily for 8 days. Period 2: Tenofovir disoproxil fumarate 300 mg daily for 16 days + rilpivirine 150 mg daily either days 1–8 or days 9–16 (n = 15). 6. Period 1: Norethindrone/ethinylestradiol 1/0.035 mg in three 21-day cycles + rilpivirine 25 mg daily on days 1–15 of the third cycle (n = 18). 7. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Ketoconazole 400 mg daily for 22 days + rilpivirine 150 mg daily days 12–22. 8. Period 1: Rilpivirine 150 mg daily for 10 days. Period 2: Lopinavir/ritonavir 400/100 mg twice daily for 20 days + rilpivirine 150 mg days 11–20 (n = 14). 9. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Omeprazole 20 mg daily for 22 days + rilpivirine 150 mg on days 12–22 (n = 16). 10. Period 1: Paracetamol 500 mg, single dose. Period 2: Rilpivirine 150 mg daily for 12 days + paracetamol 500 mg single dose on day 11 (n = 16). 11. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Rifabutin 300 mg daily for 11 days. Period 3: Rilpivirine 150 mg + rifabutin 300 mg daily for 11 days (n = 18). 12. Period 1: Sildenafil 50 mg, single dose. Period 2: Rilpivirine 75 mg daily for 12 days + sildenafil 50 mg single dose on day 12 (n = 16). 13. Period 1: Sofosbuvir/velpatasvir 400/100 mg daily for 8 days. Period 2: Emtricitabine/rilpivirine/tenofovir disoproxil fumarate 200/25/300 mg + sofosbuvir/velpatasvir 400/100 mg daily for 8 days (n = 24). 14. Period 1: Rilpivirine 25 mg daily for 14 days. Period 2: Tenofovir alafenamide fumarate 25 mg daily for 14 days. Period 3: Rilpivirine 25 mg + tenofovir alafenamide fumarate 25 mg daily, for 14 days (n = 17). 15. Stable methadone dose (60–150 mg daily) for 25 days + rilpivirine 25 mg daily on days 15–25 (n = 13). (b) Impact of co-medications on oral rilpivirine pharmacokinetics from drug–drug interaction crossover studies in healthy volunteers. 1. Period 1: Atorvastatin 40 mg daily for 4 days. Period 2: Rilpivirine 150 mg daily for 15 days + atorvastatin 40 mg daily days 12–15 (n = 16). 2. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Darunavir/ritonavir 800/100 mg daily for 22 days + rilpivirine 150 mg daily days 12–22 (n = 16). 3a. Period 1: Cabotegravir 30 mg daily for 12 days. Period 2: Rilpivirine 25 mg daily for 11 or 12 days. Period 3: Cabotegravir 30 mg daily + rilpivirine 25 mg daily for 12 days (n = 11). 3b. Period 1: Dolutegravir 50 mg daily for 5 days. Period 2: Rilpivirine 25 mg daily for 11 or 12 days. Period 3: Dolutegravir 50 daily + rilpivirine 25 mg daily for 5 days (n = 16). 4. Period 1: Grazoprevir/elbasvir 200/50 mg daily for 8 days. Period 2: Rilpivirine 25 mg daily for 11 days. Period 3: Grazoprevir/elbasvir 200/50 mg daily + rilpivirine 25 mg daily for 9 days (n = 20). 5. Period 1: Rilpivirine 150 mg daily for 8 days. Period 2: Tenofovir disoproxil fumarate 300 mg daily for 16 days + rilpivirine 150 mg daily either days 1–8 or days 9–16 (n = 15). 6. Period 1: Rilpivirine 150 mg single dose. Period 2: Rilpivirine 150 mg single dose 2 h after famotidine 40 mg single dose (n = 24). 7. Period 1: Rilpivirine 150 mg daily. Period 2: Ketoconazole 400 mg daily for 22 days + rilpivirine 150 mg daily days 12–22 (n = 14). 8. Period 1: Rilpivirine 150 mg daily for 10 days. Period 2: Lopinavir/ritonavir 400/100 mg twice daily for 20 days + rilpivirine 150 mg days 11–20 (n = 14). 9. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Omeprazole 20 mg daily for 22 days + rilpivirine 150 mg on days 12–22 (n = 16). 10. Period 1: Rilpivirine 150 mg daily for 11 days. Period 2: Rifabutin 300 mg daily for 11 days. Period 3: Rilpivirine 150 mg + rifabutin 300 mg daily for 11 days (n = 18). 11. Period 1: Rilpivirine 150 mg daily. Period 2: Rilpivirine 150 mg daily + rifampicin 600 mg daily (n = 16). 12. Period 1: Sildenafil 50 mg, single dose. Period 2: rilpivirine 75 mg daily for 12 days + sildenafil 50 mg single dose on day 12 (n = 16). 13. Period 1: Sofosbuvir/velpatasvir 400/100 mg daily for 8 days. Period 2: Emtricitabine/rilpivirine/tenofovir disoproxil fumarate 200/25/300 mg + sofosbuvir/velpatasvir 400/100 mg daily for 8 days (n = 24). Data are presented as area under the curve (squares) and trough plasma concentration (triangles) geometric mean ratios + 90% confidence intervals for rilpivirine with and without co-medication. The bioequivalence margin (0.8–1.25) is indicated by dashed vertical lines. CAB cabotegravir, DRV/RTV darunavir/ritonavir, DTG dolutegravir, GS-331007 metabolite of sofosbuvir, GZR/EBR grazoprevir/elbasvir, LPV/RTV lopinavir/ritonavir, NOR/EE norgestrel/ethinylestradiol, RPV rilpivirine, sd single dose, SOF/VEL sofosbuvir/velpatasvir, TAF tenofovir alafenamide, TDF tenofovir disoproxil fumarate [, –83, 88, 95, 96].

Fig. 4

DDI profiles of oral cabotegravir and rilpivirine or intramuscular cabotegravir plus rilpivirine when considering non-HIV co-medications (n = 725) listed in the University of Liverpool HIV drug interaction website [68]. DDI drug–drug interaction