Background:This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of the first-in-class dual mammalian target of rapamycin complex (mTORC)1/mTORC2 inhibitor, AZD8055.Methods:Patients with advanced solid malignancies or lymphomas were recruited into this phase I, open-label, dose-escalation study of AZD8055 starting at 10 mg twice-daily oral dosing (BID).Results:Forty-nine patients received AZD8055. Dose-limiting toxicities were reported at 40 mg (n=1), 90 mg (n=1) and 120 mg (n=3) BID; all were grade 3 rises in transaminases, reversible in all patients, apart from one who had liver metastases. The maximum tolerated dose was defined as 90 mg BID. The most frequent adverse events assessed to be related to AZD8055 were increased alanine aminotransferase (22%), increased aspartate aminotransferase (22%) and fatigue (16%). AZD8055 was rapidly absorbed (median tmax ∼0.5 h) and exposure increased with increasing doses. Seven patients had stable disease for ⩾4 months. Partial metabolic responses, assessed by fluorodeoxyglucose positron emission tomography, were observed at ⩾40 mg BID (n=8 at day 35).Conclusion:The maximum tolerated dose for AZD8055 is 90 mg BID. Apart from elevated transaminases, which occurred at most dose levels, the drug had an acceptable toxicity profile; however, no RECIST responses were seen.

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The pharmacokinetics of gentamicin were evaluated in 50 children and adolescents during a multiple dose course of therapy. Parameters of a 2-compartment pharmacokinetic model were derived from serial serum concentrations and urinary excretion rates measured for up to 11 days following the last dose of gentamicin administered to 10 of these patients. These parameters were used to simulate changes in serum concentrations and half-lives that would occur during a standard 6-hour dosing interval with continuous dosing. The data indicated that the half-life for decline in serum concentrations after the first dose was 76 +/- 8% of the half-life at steady-state, and that the half-life after the fourth dose exceeded 90% of the steady-state half-life. These underestimations of the steady-state serum half-life were incorporated into a 1-compartment model to simulate steady-state peak and nadir serum concentrations by using pharmacokinetic parameters measured after the first dose of gentamicin administered to 40 patients. Steady-state serum concentrations predicted by the true 1-compartment model and by the adjusted model were compared with concentrations measured at steady-state. The concentrations predicted by the former model were significantly different from and consistently less than measured concentrations. Concentrations predicted by the adjusted model were not significantly different from concentrations measured at steady-state. These data indicate that the new model offers a simple and more accurate method of simulating steady-state concentrations from pharmacokinetil for individualising therapy.

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