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Pharmacokinetics (PK) and tolerability of cabotegravir (CAB) and rilpivirine (RPV) long-acting (LA) intramuscular (IM) injections to the vastus lateralis (lateral thigh) muscles of healthy adult participants

Title
Pharmacokinetics (PK) and tolerability of cabotegravir (CAB) and rilpivirine (RPV) long-acting (LA) intramuscular (IM) injections to the vastus lateralis (lateral thigh) muscles of healthy adult participants
Presenter
Kelong Han
Authors
K. Han * (1), J.S. Shaik (1), H. Crauwels (2), C. Leemereise (3), G. Bontempo (4), B. Win (5), C. Seal (1), R. DeMoor (1), O. Upadhyay (1), V. Chounta (6), W. Spreen (4), S.L. Ford (7)
Institutions
(1) GlaxoSmithKline, Collegeville, United States, (2) Janssen Research and Development, Beerse, Belgium, (3) GlaxoSmithKline, Amersfoort, Netherlands, the, (4) ViiV Healthcare, Research Triangle Park, United States, (5) GlaxoSmithKline, Stevenage, United Kingdom, (6) ViiV Healthcare, Brentford, United Kingdom, (7) GlaxoSmithKline, Research Triangle Park, United States

BACKGROUND: CAB + RPV LA IM gluteal injections monthly and every 2 months demonstrated efficacy for maintaining HIV viral suppression and were well tolerated. Vastus lateralis thigh muscle could be a potential alternative site of administration due to injection fatigue, intolerability, or inaccessibility of the gluteal muscle or in future applications allowing self-administration. CAB and RPV PK and participant tolerability were evaluated following single IM injections to the lateral thigh; preliminary results are presented.
METHODS: Healthy adult participants received 4 weeks of daily oral CAB 30mg and RPV 25mg, followed by 10-14 day washout and single 3-mL IM injections of CAB LA 600mg and RPV LA 900mg to contralateral vastus lateralis muscles. Safety, tolerability, and sparse PK were collected through 52 weeks post-injection. PK parameters were estimated using noncompartmental analysis (NCA).
RESULTS: Fifteen participants (6 females) enrolled with median age 33 years, weight 93.6 kg, and BMI 31.4 kg/m2. One female participant withdrew during oral dosing due to pregnancy. Injection site reactions (ISRs) occurred in 14/14 participants: 12/14 (86%) Grade 1 (mild) and 2/14 (14%) Grade 2 (moderate), most resolving in 3-7 days. Most common ISRs were pain (14/14 [100%]), erythema (8/14 [57%]), induration (7/14 [50%]), bruising (4/14 [29%]), warmth (3/14 [21%]), and pruritis (2/14 [14%]). Observed CAB and RPV concentration-time profiles are shown in the Figure. Plasma concentrations at Weeks 4 and 8 were 15- and 5.3-fold above protein-adjusted IC90 (PA-IC90) for CAB and 4.7- and 2.4-fold for RPV, respectively.


Table. Preliminary plasma PK parameters after single IM administration of CAB LA 600 mg (3 mL) and RPV LA 900 mg (3 mL) to the lateral thigh muscles in healthy adult participants

CmaxTmaxAUClastConcentration
At Week 4		Concentration
At Week 8
CAB LA
(n=14)		3.38 mg/mL
(66%)		1 week
(1, 8)		3832 h*mg/mL
(22.8%)		2.56 mg/mL
(38.9%)		0.88 mg/mL
(84.2%)
RPV LA
(n=14)		93.5 ng/mL
(37.7%)		0.8 week
(0.42, 4)		145000 h*ng/mL
(33.1%)		56.7 ng/mL
(28.5%)		30.8 ng/mL
(37.7%)
PK parameters were estimated using noncompartmental analysis. Values displayed are geometric mean (CV%) except for Tmax, which is displayed as median (range). Plasma concentrations below LLOQ were omitted. AUClast: area under concentration-time curve from time 0 to the last observation above LLOQ. Cmax: maximum plasma concentration post IM injection. Tmax: time at which Cmax occurs.

CONCLUSIONS: CAB and RPV LA IM injections to the vastus lateralis muscle were well tolerated with mild-to-moderate ISRs, and showed favorable plasma PK profiles, supporting further evaluation of thigh IM administration in target population(s).

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