Journal of pharmaceutical sciences
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The main objective of this study was to investigate the feasibility of delivery of propofol phosphate (PP), a prodrug of propofol, via transdermal route using iontophoresis in combination with chemical permeation enhancers (CPEs). PP, a prodrug, was synthesized and its structure was characterized. In vitro passive and iontophoretic drug transport studies were carried out using Franz diffusion cell across freshly excised hairless rat skin at different concentrations of PP in combination with CPE. ⋯ The amount of propofol present in plasma samples in control group (passive) was below the detectable levels at all the time points during the study. The plasma concentration-time profile of iontophoresis group of rats was fit to a noncompartmental model and the pharmacokinetic parameters were calculated. These studies suggest the plausibility of achieving therapeutically relevant levels of propofol when delivered via transdermal route by combining iontophoresis with CPE.
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The acetaminophen dosage schedule in pediatric patients below 12 years of age for the over-the-counter (OTC) monograph is one of the many issues being evaluated and discussed in the development of the Proposed Rule for Internal Analgesic, Antipyretic, and Anti-rheumatic drug products. The dosage regimen based on age and weight, with instructions that weight-based dosage should be used if a child's weight is known, is currently being assessed by the agency. This review summarizes the available pharmacokinetic and pharmacodynamic (fever reduction) data of oral acetaminophen in pediatric patients of 6 months to 12 years of age. ⋯ The sulfation pathway plays a more important role in metabolizing acetaminophen than the glucuronidation pathway in younger children as compared with older children and adults. The pharmacokinetic exposure of acetaminophen in pediatric patients of 6 months to 12 years of age given oral administration of 10-15 mg/kg is within the adult exposure range given the OTC monograph dose. The antipyretic effect of acetaminophen is dose dependent and appears to be better than placebo at the dose range of 10-15 mg/kg in pediatric patients of 6 months to 12 years of age.
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Biologics, specifically monoclonal antibody (mAb) drugs, have unique pharmacokinetic (PK) and pharmacodynamic (PD) characteristics as opposed to small molecules. Under the paradigm of model-based drug development, PK-PD/clinical response models offer critical insight in guiding biologics development at various stages. ⋯ Examples of using TMDD, PK-PD, and meta-analysis in helping starting dose determination in first-in-human studies and dosing regimen optimization in phase II/III trials are discussed. Instead of covering the entirety of model-based biologics development, this review focuses on the guiding principles and the core mathematical descriptions underlying the PK or PK-PD models most used.
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The pharmacokinetics and pharmacodynamics of fospropofol (FP) disodium injection, propofol emulsion (PE), and cyclodextrin-enabled propofol (CDP) solution following bolus parenteral administration in dogs was evaluated. Three healthy male beagle dogs were treated in a three-way cross-over study (14 day washout period) with 6 mg/kg propofol equivalents. Blood samples were collected predose and at 16 points postdose through 1440 min and analyzed for propofol and FP, when appropriate. ⋯ The effect site concentrations at 50% the maximum EEG effect for the FP and CDP formulations were approximately one-half that of the PE formulation. Onset and duration of anesthesia are correlated with modeled effect site propofol concentrations. The implications of formulation on pain on injection and propofol activity are discussed.
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Previously, our laboratory reported that cyclic peptide prodrugs of the opioid peptide H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (DADLE) are metabolized by cytochrome P450 (CYP450) enzymes, which limits their systemic exposure after oral dosing to animals. In an attempt to design more metabolically stable cyclic prodrugs of DADLE, we synthesized analogs of DADLE cyclized with a coumarinic acid linker (CA; CA-DADLE), which contained modifications in the amino acid residues known to be susceptible to CYP450 oxidation. Metabolic stability and metabolite identification studies of CA-DADLE and its analogs were then compared using rat liver microsomes (RLM), guinea pig liver microsomes (GPLM), and human liver microsomes (HLM), as well as recombinant human recombinant cytochrome P450 3A4 (hCYP3A4). ⋯ When CA-DADLE was incubated with hCYP3A4, similar oxidative metabolism of the peptide was observed. In contrast, incubation of the CA-DADLE analogs with hCYP3A4 showed that these amino-acid-modified analogs are not substrates for this CYP450 isozyme. These results suggest that the amino-acid-modified analogs of CA-DADLE prepared in this study could be stable to metabolic oxidation by CYP3A4 expressed in human intestinal mucosal cells.