Hypophosphatasia (HPP) is a rare, inherited metabolic disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Efzimfotase alfa (ALXN1850) is a second-generation TNSALP enzyme replacement therapy in development for HPP. This first-in-human open-label, dose-escalating phase 1 trial evaluated efzimfotase alfa safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity.
View Article and Find Full Text PDFSelumetinib is clinically used for pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. Until recently, selumetinib had to be taken twice daily, after 2 hours of fasting and followed by 1 hour of fasting, which could be inconvenient. This population analysis evaluated the effect of low- and high-fat meals on the pharmacokinetic (PK) parameters of selumetinib and its active metabolite N-desmethyl selumetinib.
View Article and Find Full Text PDFHypophosphatasia is a rare metabolic disease resulting from variant(s) in the gene-encoding tissue-nonspecific isozyme of alkaline phosphatase. In this 13-week, phase 2a, multicenter, randomized, open-label, dose-response study (ClinicalTrials.gov: NCT02797821), the pharmacokinetics of asfotase alfa, an enzyme replacement therapy approved for the treatment of hypophosphatasia, was assessed in adult patients with pediatric-onset hypophosphatasia.
View Article and Find Full Text PDFThe purpose of this study was to predict a safe starting dose of AMG 181, a human anti-α 4 β 7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic (PK) and pharmacodynamic (PD) data. A two-compartment model with parallel linear and target-mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK.
View Article and Find Full Text PDFIL-15 is a proinflammatory cytokine that plays an important role in the development and activation of NK cells and is a potential target for inflammatory disease therapy. Studies conducted in IL-15- and IL-15R knockout mice identified IL-15 as an important cytokine for NK cell homeostasis. Consistent with this information derived from genetically modified mice, we demonstrated that neutralizing IL-15 with a mouse anti-mouse IL-15 mAb (M96) depletes C57BL/6 mouse NK cells.
View Article and Find Full Text PDFAMG X, a human neutralizing monoclonal antibody (mAb) against a soluble human protein, caused thrombocytopenia, platelet activation, reduced mean arterial pressure, and transient loss of consciousness in cynomolgus monkeys after first intravenous administration. In vitro, AMG X induced activation in platelets from macaque species but not from humans or baboons. Other similar mAbs against the same pharmacological target failed to induce these in vivo and in vitro effects.
View Article and Find Full Text PDFCurr Pharm Biotechnol
June 2012
Pharmacokinetic/pharmacodynamic (PK/PD) modeling & simulation (M&S) provides quantitative assessment of dose/exposure-response relationships with extensive applications at the late stage drug development as well as during regulatory decision making. However, at preclinical and early phase clinical drug development, the importance of PK/PD M&S has not been as widely recognized. We reviewed selected PK/PD M&S literatures in order to convey importance of M&S in these early development phases.
View Article and Find Full Text PDFAMG 900 is a small molecule being developed as an orally administered, highly potent, and selective pan-aurora kinase inhibitor. The aim of the investigations was to characterize in vitro and in vivo pharmacokinetic (PK) properties of AMG 900 in preclinical species. AMG 900 was rapidly metabolized in liver microsomes and highly bound to plasma proteins in the species tested.
View Article and Find Full Text PDFJ Investig Dermatol Symp Proc
May 2007
Immunologic limitations make it difficult to study the pharmacokinetic effects of human tumor necrosis factor (TNF) blockers in murine models. To counter this, we have studied the pharmacokinetics in mice of two murine analogs of human TNF blockers, a murine p75-FC fusion protein (analogous to etanercept), and the rat MP6-XT22 anti-murine TNF mAb (analogous to infliximab). We analyzed the pharmacokinetics of the murine p75-Fc protein and MP6-XT22 antibody in mice that were uninfected and in mice with disseminated candidiasis in order to confirm dosing strategies and interpret future studies evaluating the efficacy and tolerability of these agents in mice.
View Article and Find Full Text PDFBackground: As the comparative pharmacokinetics and pharmacodynamics of lansoprazole and rabeprazole have not previously been studied, we set out in this study to compare the pharmacokinetics and pharmacodynamics of single and repeated daily doses of lansoprazole 15 mg and 30 mg with those of rabeprazole 10 mg and 20 mg.
Methods: This was an open-label, randomised, crossover, two-centre study in 72 healthy volunteers. Each subject received each of the four treatments for 5 days, with 2-week washout periods.
Objective: The pharmacokinetic profiles of single doses of lansoprazole 15- and 30-mg sachets for suspension were compared with those of corresponding doses of lansoprazole oral capsules.
Methods: Healthy adult male and female subjects were randomized (1:1 ratio) into 2 Phase 1, open-label, single-dose, 2-sequence, 2-period complete crossover studies. In the first study, each subject received 1 lansoprazole 15-mg sachet mixed with water and 1 lansoprazole 15-mg oral capsule; in the second study, each subject received 1 lansoprazole 30-mg sachet mixed with water and 1 lansoprazole 30-mg oral capsule.
The present study was designed to assess the effect of the addition of zonisamide (ZNS) on lamotrigine (LTG) disposition and the safety of the combination under steady-state conditions in patients with epilepsy. A secondary objective was to characterize ZNS pharmacokinetics (PK) in the presence of LTG. Twenty subjects (male and female 18 to 55 years old) stabilized on LTG monotherapy (150-500 mg/d) took part in a 2-center, open-label, 1-way drug interaction study.
View Article and Find Full Text PDFThis study was designed to measure the effect of the addition of zonisamide on phenytoin pharmacokinetics under steady-state conditions in patients with epilepsy. Nineteen patients stabilized under phenytoin monotherapy were included in a 3-center, open-label, 1-way drug interaction trial. Zonisamide was gradually increased to 400 mg/day, taken twice daily.
View Article and Find Full Text PDFObjectives: To evaluate the pharmacokinetics, pharmacodynamics, symptom relief efficacy, and tolerability of lansoprazole in adolescents between 12 and 17 years of age with gastroesophageal reflux disease (GERD).
Methods: Adolescents with symptomatic, endoscopically and/or histologically proven GERD were enrolled in this multicenter, double-blind trial and randomized to lansoprazole 15 mg or 30 mg once daily for 5 days.
Results: Sixty-three adolescents were enrolled in the study.
Objectives: To evaluate the pharmacokinetics and pharmacodynamics of lansoprazole in children between 1 and 11 years of age with gastroesophageal reflux disease (GERD).
Methods: In a multicenter, open-label trial of pediatric patients with symptomatic GERD, children were assigned, based on their weight, to receive lansoprazole 15 mg (patients weighing < or = 30 kg) or lansoprazole 30 mg (patients weighing > 30 kg) once daily. The effects of lansoprazole on 24-hour median intragastric pH, the percentages of time intragastric pH was above 3 and 4, and pharmacokinetic parameters were assessed at the day-5 visit and compared to baseline.