In-vitro Interaction of a Novel Immunosuppressant, FK 506, and Antacids

Abstract-The effect of selected antacids on the amount ofFK 506 in solution in simulated gastric juice has been studied. FK 506 (2·5 mg) was incubated in 100 mL simulated gastric fluid (SGF) with the equivalent of 500 mg of various antacids. The addition of Mylanta and Turns resulted in 14 and 30'1., loss of FK 506, respectively, in 24 h; 98% loss was observed in 12 h in the presence of Mag-Ox; 100'Yo loss was observed in the presence of magnesium oxide powderin 2 h. The loss ofFK 506 from these solutions appears to be due to a pH mediated degradation of FK 506. The addition of aluminium hydroxide gel USP (Roxane) to the FK 506 solution resulted in a 35°;;, loss within 2 min but no further loss was noted for 24 h. indicative of adsorption ofFK 506. These results suggest that until additional in-vivo studies are carried out. it is prudent not to dose FK 506 and antacids at the same time to avoid potential interactions

Approaches to dose finding in neonates, illustrating the variability between neonatal drug development programs

Drug dosing in neonates should be based on integrated knowledge concerning the disease to be treated, the physiological characteristics of the neonate, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. It is critically important that all sources of information be leveraged to optimize dose selection for neonates. Sources may include data from adult studies, pediatric studies, non-clinical (juvenile) animal models, in vitro studies, and in silico models. Depending on the drug development program, each of these modalities could be used to varying degrees and with varying levels of confidence to guide dosing. This paper aims to illustrate the variability between neonatal drug development programs for neonatal diseases that are similar to those seen in other populations (meropenem), neonatal diseases related but not similar to pediatric or adult populations (clopidogrel, thyroid hormone), and diseases unique to neonates (caffeine, surfactant). Extrapolation of efficacy from older children or adults to neonates is infrequently used. Even if a disease process is similar between neonates and children or adults, such as with anti-infectives, additional dosing and safety information will be necessary for labeling, recognizing that dosing in neonates is confounded by maturational PK in addition to body size