What is the significance of the pharmacokinetic profile and potential drug–drug interactions of long-acting intramuscular cabotegravir and rilpivirine?

Figures & data

Figure 1. Illustration of the flip-flop pharmacokinetics after intramuscular administration for which the rate of elimination (kel) is faster than the rate of absorption (ka) as opposed to oral administration.

Figure 2. Drug profile after oral (left) and intramuscular (right) administration and impact of inducers or inhibitors on the elimination half-life.

Table 1. Proportion of individuals with cabotegravir and rilpivirine concentrations above the efficacy threshold during the intramuscular administration dosing interval for various simulated DDI scenarios. Reprinted from reference [7], with permission from Oxford University Press License.

Dosage of intramuscular cabotegravir/rilpivirine	Efficacy threshold [ng/mL]	Estimated proportion of individuals above the efficacy threshold during the dosing interval [%]
Drug-drug interaction scenarios with rifabutin (300 mg – steady state)
Cabotegravir (600 mg – loading dose)	664	60
Cabotegravir (400 mg – maintenance dose Q4W)		100
Cabotegravir (600 mg – maintenance dose Q8W)		94
Dosage adjustment to overcome drug-drug interaction with rifabutin (300 mg – steady state)
Cabotegravir (600 mg – loading dose Q2W)	664	97
Cabotegravir (400 mg – maintenance dose Q4W)		100
Drug-drug interaction scenarios with rifabutin (300 mg – steady state)
Rilpivirine (900 mg – loading dose)	50	0
Rilpivirine (600 mg – maintenance dose Q4W)		20
Rilpivirine (900 mg – maintenance dose Q8W)		0
Dosage adjustment to overcome drug-drug interaction with rifabutin (300 mg – steady state)
Rilpivirine (900 mg – loading dose Q2W)	50	13
Rilpivirine (900 mg – maintenance dose Q8W 25 mg – oral QD)		62
Rilpivirine (600 mg – maintenance dose Q4W 25 mg – oral QD)		92

Abbreviations: PO, oral administration; QD, administered once a day; Q2W, administration every 2 weeks; Q4W, administration every 4 weeks; Q8W, administration every 8 weeks.

Bettonte S, Berton M, Stader F, et al. Management of drug-drug interactions between long-acting cabotegravir and rilpivirine and comedications with inducing properties: a modelling study. Clin Infect Dis. 2022;76(7):1225–1236. [epub ahead print]. doi: 10.1093/cid/ciac901

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