Minireview Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper

ABSTRACT An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. To identify the key absorption, distribution, metabolism, and excretion (ADME) issues worth examining when developing an ADC and to find optimal scientifically based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an ADC ADME working group in early 2014. This white paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs

Efficacy and Safety of Aminoglycosides Once-a-day - Experimental and Clinical-data

In vitro and animal data show that the efficacy of an aminoglycoside is primarily related to its serum peak levels and AUC, whereas its toxicity is critically dependent upon the schedule of the administration of the daily dose as well as the duration of the treatment and the total amount of drug administered. The reduction of toxicity by intermittent dosing, e.g. once-a-day dosing (q.d.) versus splitting the daily dose in multiple administrations is connected with the saturable character of the aminoglycoside transport within inner ear and renal tissues. Clinical trials have been conducted in various types of infections in order to investigate the efficacy and tolerance of aminoglycosides q.d. Using conventional criteria of evaluation, this mode of administration was found to be equally efficacious and marginally less toxic than aminoglycosides in conventional dosing regimens. We have studied the pharmacokinetics and the early signs of renal (phospholipiduria) and auditory (high frequency audiometry) alterations of aminoglycosides given q.d. and by conventional dosage schedues to patients with pelvic inflammatory disease. It was shown that netilmicin and amikacin were better tolerated q.d. than after t.i.d. or b.i.d. administration. In addition, amikacin induced less alterations than netilmicin