Cabotegravir pharmacokinetics
Cabotegravir, a second generation INSTI binds to the active site of HIV
integrase enzyme and inhibits the cDNA strand transfer step. Trough
concentration (Ctrough) is the most common efficacy
surrogate for INSTIs. LAI cabotegravir for HIV prevention is dosed at
600mg/3ml with the first 2 injections administered 4 weeks apart,
followed thereafter by an injection every 8 weeks. This is the same
dosing schedule for 2-monthly HIV treatment in combination with LAI
rilpivirine. Dosing can be administered within a window +/-7 days of the
planned date of injection . A 4-week oral lead-in (OLI) of daily oral
cabotegravir 30 mg and rilpivirine 25 mg is offered, but not essential,
to ensure tolerability before transitioning to injections.
Intramuscular cabotegravir has a median time to maximal plasma
concentration (Tmax) of 7 days and reaches steady state
after 44 weeks . Cabotegravir is highly protein bound
(>99.8%) with a volume of distribution is 12.3 L. Both
oral and intramuscular cabotegravir are largely metabolised hepatically
by UDP-glucuronyltransferase (UGT)-1A1 with a minor contribution from
Cytochrome P450 (CYP) 1A9 and are excreted largely in the urine and
small amount in bile/faeces . Cabotegravir does not inhibit or induce
CYP isoforms, glucuronidation enzymes, P-glycoprotein (P-gp), breast
cancer resistance protein (BCRP), organic anion transporting polypeptide
(OATPs) 1B1/1B3, organic cation transporter (OCT) or other
enzymes/transporters. However, cabotegravir inhibits the renal
transporter OAT1 and OAT3 and can increase exposures of OAT1 and OAT3
substrate such as ciprofloxacin, tenofovir disoproxil fumarate,
cefuroxime, however this is to a non-clinically significant level.
Intramuscular cabotegravir has an elimination half-life 6-12 weeks,
compared to 41 hours for oral cabotegravir. As with other intramuscular
long-acting drugs cabotegravir exhibits ‘flip-flop’ pharmacokinetics,
with the slow absorption rate contributing to the prolonged elimination
half-life . Due to the very long half-life of LAI cabotegravir some
individuals have detectable levels a year after a single injection. If
injections are missed or HIV treatment is stopped oral ART must be
re-initiated a maximum of 2 months after the last injection to prevent
drug resistance. There is no dose adjustment in renal impairment and no
dose-adjustment is needed in mild-moderate hepatic impairment .