If HIV-patients are unconscious or cannot swallow tablets for other reasons, antiretroviral medication is often crushed and dissolved prior to administration. Crushing can influence pharmacokinetics (PK) leading to altered drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Currently, there is no information about crushing the branded fixed-dose combination of dolutegravir/abacavir/lamivudine (TRI), therefore crushing TRI is not recommended. In addition, a PK interaction between dolutegravir (DTG) and enteral nutrition is possible, based on the known interaction between DTG and cations in antacids and supplements.
An open-label, 3-period, randomized, cross-over, trial in 22 healthy volunteers was conducted. Subjects randomly received a single dose of TRI with a 7-day washout period. Reference treatment A: TRI whole tablet fasting, intervention treatments B: crushed and suspended TRI fasting and C: crushed and suspended TRI, followed by drinking drip feed (250kcal) within 5 minutes after TRI intake. To show bioequivalence between reference A and B and C a 48-h PK profile was measured for DTG. Geometric mean ratios (GMR) with 90% confidence interval (CI) for AUC0-inf and Cmax were calculated. Bioequivalence was accepted when the 90% CI was within 80-125% for AUC and Cmax. Safety and tolerability were evaluated.
22 healthy volunteers (21 Caucasian and 1 mixed-race, 10 female), 25 (18-54) years and BMI 23 (20-27) kg/m2 (median (range)) completed the trial. For crushed TRI vs whole tablet, the GMR (90% CI) of DTG Cmax was 129% (123-136), of DTG AUC0-inf 126% (119-132) and DTG half-life 101% (97-104). For crushed TRI with enteral nutrition vs whole tablet, the GMR (90% CI) of DTG Cmax was 122% (115-128), of DTG AUC0-inf 118% (112-125) and DTG half-life 98% (95-102). No SAEs were reported during the trial.
AUC0-inf and Cmax fell outside the predefined bioequivalence range. DTG exposure was 26% higher after crushing and 18% higher after crushing and intake with enteral nutrition. The maximum concentrations showed the same trend. The half-life was similar in all treatments, therefore increased DTG exposure is probably caused by enhanced absorption. Enteral nutrition did not negatively affect DTG absorption. Although no dose-limiting toxicity of DTG is observed to date, caution is warranted if chronic administration of crushed TRI is needed.