A Population Pharmacokinetic Assessment of the Effect of Food on Selumetinib in Patients with Neurofibromatosis Type 1-Related Plexiform Neurofibromas and Healthy Volunteers.

Selumetinib 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. The dataset comprised 511 subjects from 15 clinical trials who received ≥1 dose of selumetinib and provided ≥1 measurable postdose concentration of selumetinib and N-desmethyl selumetinib. A 2-compartment model with sequential 0- and 1st-order delayed absorption and 1st-order elimination adequately described selumetinib PK characteristics. A 1-compartment model reasonably described N-desmethyl selumetinib PK characteristics over time simultaneously with selumetinib. Selumetinib geometric mean area under the concentration-time curve ratio (1-sided 90% confidence interval [CI] lower bound) was 76.9% (73.3%) with a low-fat meal and 79.3% (76.3%) with a high-fat meal versus fasting. The lower bound of the 1-sided 90% CI demonstrated a difference of <30% between fed and fasted states. Considering the flat exposure-response relationship within the dose range (20-30 mg/m2), the observed range of exposure, and the variability in the SPRINT trial, this was not considered clinically relevant.

Pharmacokinetics of Asfotase Alfa in Adult Patients With Pediatric-Onset Hypophosphatasia.

Hypophosphatasia 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. In total, 27 adults were randomly assigned 1:1:1 to a single subcutaneous dose of asfotase alfa (0.5, 2.0, or 3.0 mg/kg) during week 1. From week 3 to week 9, patients received 0.5, 2.0, or 3.0 mg/kg subcutaneously 3 times per week (equivalent to 1.5, 6.0, or 9.0 mg/kg/wk, respectively). Noncompartmental analysis revealed exposure (maximum concentration in the dosing interval and area under the concentration-time curve from time 0 to infinity) to asfotase alfa increased between single- and multiple-dose administration and with increasing doses; however, extensive interindividual variability was observed in the concentration-time profiles within each dose cohort. Median terminal elimination half-life was ≈5 days following multiple-dose administration, with steady state achieved by approximately day 29. Dose-normalized exposure data indicated that asfotase alfa activity was approximately dose-proportional within the studied dose range. Additionally, dose-normalized exposure was comparable across body mass index categories of <25, ≥25 to <30, and ≥30 kg/m2 , indicating that asfotase alfa dosing bioavailability was consistent in these patients, including those who were obese. These data, together with previously published pharmacodynamic results in this study population, support the use of asfotase alfa at the recommended dose of 6 mg/kg/wk in adults with pediatric-onset hypophosphatasia.

Prediction of clinical pharmacokinetics of AMG 181, a human anti-α 4 ß 7 monoclonal antibody for treating inflammatory bowel diseases.

The purpose of this study was to predict a safe starting dose of AMG 181, a human anti-α 4 ß 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. An E max PD model was used to relate AMG 181 concentration and free α 4 ß 7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg(-1) in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α 4 ß 7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day(-1) and 2900 mL, respectively. The estimated EC50 for free α 4 ß 7 receptor was 14 ng·mL(-1). At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α 4 ß 7 receptor EC10. Predictions for both C max and AUC matched with those observed in the first-in-human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone.

Clinical pharmacology of AMG 181, a gut-specific human anti-α4ß7 monoclonal antibody, for treating inflammatory bowel diseases.

AIMS: AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study. METHODS: Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α4 ß7 receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose. RESULTS: Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear ß-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 µg ml(-1) . The PD effect on α4 ß7 RO showed an EC50 of 0.01 µg ml(-1) . Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed. CONCLUSIONS: AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.

Homeostasis of human NK cells is not IL-15 dependent.

IL-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. An mAb directed against macaque IL-15 (Hu714MuXHu) was manufactured and demonstrated to block IL-15-induced activation of nonhuman primate (NHP) NK cells in vitro. Neutralization of macaque IL-15 by parenteral administration of Hu714MuXHu reduces (>95%) circulating NK cell counts in NHPs. A blocking mAb directed against human IL-15 (huIL-15; AMG 714) was manufactured. Unexpectedly, when human subjects were treated with the blocking anti-IL-15 Ab AMG 714 in clinical trials, no reductions in circulating NK cell counts were observed despite achieving significantly higher exposures than the levels of Hu714MuXHu needed to cause NK cell count reductions in NHPs in vivo. Both AMG 714 and Hu714MuXHu are able to block huIL-15 activity in a human T cell blast proliferation and IFN-γ production assay. Both Abs block huIL-15-mediated Stat5 activation and CD69 expression in human NK cells. Collectively, these results demonstrate that NK cell homeostasis is obligatorily dependent upon IL-15 in both mice and NHPs, but that IL-15 is dispensable for maintenance of circulating human NK cells.

Off-target platelet activation in macaques unique to a therapeutic monoclonal antibody.

AMG 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. In addition, the target protein was known to not be expressed on platelets, suggesting that platelet activation occurred through an off-target mechanism. AMG X bound directly to cynomolgus platelets and required both the Fab and Fc portion of the mAb for platelet activation. Binding to platelets was inhibited by preincubation of AMG X with its pharmacological target or with anti-human Fc antibodies or by preincubation of platelets with AMG X F(ab')(2) or human immunoglobulin (IVIG). AMG X F(ab')(2) did not activate platelets. Thus, platelet activation required both recognition/binding of a platelet ligand with the Fab domain and interaction of platelet Fc receptors (i.e., FcγRIIa) with the Fc domain. These findings reflect the complexity of the mechanism of action of mAbs and the increasing awareness of potential for unintended effects in preclinical species.

Pharmacokinetics/pharmacodynamics model-supported early drug development.

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. We focused on the application of M&S to select and optimize lead candidates, the use of preclinical PK/PD data to project the range of clinical doses, and the development of comprehensive dose/exposure-response models that can be used to forecast the probability of achieving a target response based on Phase 1 safety, PK and biomarker information. We also reviewed several other M&S approaches that are often used in early drug development such as physiologically-based pharmacokinetic (PBPK) modeling, meta-analysis, PK-pharmacogenomics modeling, and etc. Our aims were to provide expert opinions on the practical utility of PK/PD model-based approaches that have positive impact on early decision-making with the goal of improving the success rate of early to late stage drug development.

In vitro and in vivo pharmacokinetic characterizations of AMG 900, an orally bioavailable small molecule inhibitor of aurora kinases.

AMG 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. It was a weak Pgp substrate with good passive permeability. AMG 900 exhibited a low-to-moderate clearance and a small volume of distribution. Its terminal elimination half-life ranged from 0.6 to 2.4 h. AMG 900 was well-absorbed in fasted animals with an oral bioavailability of 31% to 107%. Food intake had an effect on rate (rats) or extent (dogs) of AMG 900 oral absorption. The clearance and volume of distribution at steady state in humans were predicted to be 27.3 mL/h/kg and 93.9 mL/kg, respectively. AMG 900 exhibited acceptable PK properties in preclinical species and was predicted to have low clearance in humans. AMG 900 is currently in Phase I clinical testing as a treatment for solid tumours. Preliminary human PK results appear to be consistent with the predictions.

Pharmacokinetics of murine p75-Fc fusion protein and MP6-XT22 anti-murine TNF-alpha mAb in mice.

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. We propose that, while conducting safety or efficacy studies in murine disease models, it is reasonable to administer the murine p75-Fc protein to mice at <10 mg/kg every 4-5 days, and the MP6-XT22 antibody at 10-20 mg/kg every 4-5 days.

Comparison of the effects of single and repeated oral doses of lansoprazole and rabeprazole on ambulatory 24-hour intragastric pH in healthy volunteers.

BACKGROUND: 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. Continuous 24-hour intragastric pH and pharmacokinetics were studied on days 1 and 5. RESULTS: Mean 24-hour pH and percentage time for pH > 4 were not significantly different between lansoprazole 30 mg and rabeprazole 20 mg. Mean 24-hour pH and percentage time for pH > 4 were significantly greater after lansoprazole 30 mg and rabeprazole 20 mg than after lansoprazole 15 mg and rabeprazole 10 mg, respectively. Lansoprazole resulted in greater acid suppression during hours 0-5 on days 1 and 5, whereas rabeprazole had greater suppression during hours 11-24 on day 5. Time to maximum plasma concentration was significantly shorter for lansoprazole on both days. CONCLUSION: Lansoprazole had a consistently faster onset of action, whereas rabeprazole had a greater effect during the evening hours after 5 days of administration.

Lack of clinically significant pharmacokinetic interactions between zonisamide and lamotrigine at steady state in patients with epilepsy.

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. ZNS was gradually increased to 200 mg twice daily over a 3-week period, and 3 PK profiles were performed: on days -7 and -1 to assess the PK of oral LTG administered alone and on day 35, after 14 days of ZNS at the maximal tolerated dose, to evaluate the effect of ZNS on LTG PK and to characterize ZNS PK in the presence of LTG. Eighteen subjects completed the study. Steady-state dosing of ZNS did not significantly affect the mean Cmin (mean +/- SD: 2.8 +/- 1.4 vs 3.5 +/- 2.4 microg/mL), Cmax (5.1 +/- 3.0 vs 5.1 +/- 3.0 microg/mL), AUC0-12 (45.5 +/- 22.6 vs 50.3 +/- 32.1 microg.h/mL), and CL/F (2778.5 +/- 1368.5 vs 3052.1 +/- 2744.9 mL/h) of LTG measured before (day -1) and after (day 35) ZNS administration, respectively. Further, 90% confidence intervals for the geometric mean ratios (day 35/day -1) fell within the no-effect range of 0.80-1.25. The fraction of dose of total and unconjugated LTG excreted in urine was not significantly different between baseline and ZNS treatment, but the renal clearance of LTG decreased significantly with ZNS dosing (P = 0.01). On the other hand, the PK parameters measured for ZNS in the presence of LTG were consistent with an absence of LTG effect on ZNS PK. The coadministration of ZNS and LTG was generally well tolerated. Steady-state safety and PK of LTG and ZNS are not affected significantly when these two drugs are coadministered at clinically relevant doses, indicating that no dosage adjustment of either drug should be required when they are used in combination.

Lack of a clinically significant effect of zonisamide on phenytoin steady-state pharmacokinetics in patients with epilepsy.

This 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. Three pharmacokinetic profiles were performed: on days -7 and -1, to assess pharmacokinetic parameters of oral phenytoin administered alone, and on day 35, after 14 days of zonisamide treatment, to evaluate the effect of zonisamide on phenytoin pharmacokinetics and to characterize zonisamide pharmacokinetics in the presence of phenytoin. Fourteen patients completed the study; the coadministration of zonisamide and phenytoin was safe and well tolerated. Zonisamide did not significantly affect the mean C(min), C(max), AUC(0-12), and CL/F of phenytoin measured before and after zonisamide administration. The pharmacokinetic measures of zonisamide in the presence of phenytoin were consistent with previous reports of induction of zonisamide metabolism by phenytoin.

Comparison of the pharmacokinetics of lansoprazole 15- and 30-mg sachets for suspension versus intact capsules.

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. Administration of the 2 formulations was separated by a washout period of > or =7 days. Blood samples were collected before and after each administration to assess the pharmacokinetic parameters of lansoprazole and bioequivalence between suspension and capsule. RESULTS: Thirty-six subjects (19 males, 17 females) with a mean (SD) age of 32.0 (9.6) years and mean (SD) body weight of 68.6 (10.5) kg received lansoprazole 15 mg. Thirty-six subjects (22 males, 14 females) with a mean (SD) age of 38.0 (8.3) years and mean (SD) body weight of 75.1 (9.7) kg received lansoprazole 30 mg. The pharmacokinetic parameters of the 15- and 30-mg lansoprazole sachets for suspension were similar to those of the corresponding doses of the oral capsules. The mean (SD) values for C(max) and AUC from time 0 to infinity (AUC(0-infinity) for the lansoprazole 15-mg sachet (591.9 [242.3] ng/mL and 1614 [2065] ng.h/mL, respectively) did not differ significantly from those for the lansoprazole 15-mg capsules (578.6 [275.2] ng/mL and 1620 [2290] ng.h/mL, respectively). These parameters also did not differ significantly between the lansoprazole 30-mg sachet and 30-mg capsule: mean (SD) C(max), 1103 (428.3) and 1077 (465.6) ng/mL, respectively; mean (SD) AUC(0-infinity), 2655 (1338) and 2669 (1311) ng.h/mL, respectively. The 90% Cls for C(max) and AUC(0-infinity) ratios were contained within the 0.80 to 1.25 equivalence range, supporting bioequivalence. CONCLUSIONS: These findings suggest that the 15- and 30-mg lansoprazole sachets for suspension are bioequivalent to the corresponding doses of oral capsules. The sachet for suspension may provide an alternative route of administration to patients who have difficulty swallowing solid oral formulations.

Lansoprazole in adolescents with gastroesophageal reflux disease: pharmacokinetics, pharmacodynamics, symptom relief efficacy, and tolerability.

OBJECTIVES: 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. After lansoprazole administration, T(max) occurred at 1.6 hours in those treated with lansoprazole 15 mg and at 1.7 hours in those treated with lansoprazole 30 mg. Dose-proportional increases in lansoprazole C(max) and AUC were observed in the treatment groups. Age, weight, and gender had no significant effect on T(max), C(max), or AUC. Lansoprazole produced significant increases (P < or = 0.05) in mean 24-hour intragastric pH and the percentages of time intragastric pH was above 3 and 4. The majority of adolescents treated with lansoprazole 15 mg (69%, 22/32) or lansoprazole 30 mg (74%, 23/31) demonstrated improvement in their reflux symptoms after 5 days of treatment. Adolescents in both dosage groups exhibited reductions from baseline in the percentage of days and nights with heartburn (or other predominant symptom of GERD), the severity of heartburn, the percentage of days antacids were used, and the number of antacid tablets used per day. Pharyngitis and headache were the most commonly reported side effects among adolescents treated with lansoprazole 15 mg and 30 mg, respectively. Five patients experienced adverse events considered to be possibly treatment-related. One patient with a history of environmental allergies experienced a mild allergic reaction after 3 days of treatment with lansoprazole 15 mg. Among those treated with lansoprazole 30 mg, 4 patients each reported one occurrence of pain (toothache), diarrhea, dizziness, and rash. CONCLUSION: The pharmacokinetic parameters of lansoprazole observed in this study of adolescents are similar to those observed in studies of healthy adults. Lansoprazole 15 mg or 30 mg once daily for 5 days produces significant increases in intragastric pH, effectively relieves symptoms of reflux disease, and is well tolerated in adolescents with GERD.

Pharmacokinetics and pharmacodynamics of lansoprazole in children with gastroesophageal reflux disease.

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. RESULTS: Sixty-six children were enrolled in the study. Mean lansoprazole C(max) values of 790.9 ng/mL and 898.5 ng/mL and T(max) values of 1.5 hours and 1.7 hours were observed in the < or = 30 kg and the > 30 kg body weight treatment groups, respectively. AUC0-24 values of 1707 ng x h/mL and 1883 ng x h/mL and T1/2 values of 0.68 hours and 0.71 hours were observed in the < or = 30 kg and > 30 kg lansoprazole body weight treatment groups, respectively. There was no statistical significant difference in AUC0-24 between the two groups (P = 0.2571). After 5 days of treatment lansoprazole produced significant increases in patients' 24-hour mean intragastric pH and the percentages of time intragastric pH was above 3 and 4 compared to baseline. CONCLUSION: The observed pharmacokinetic properties of lansoprazole in children between 1 and 11 years of age with GERD were similar to those previously observed in healthy adult subjects. Lansoprazole significantly increased the mean 24-hour intragastric pH and the percentages of time intragastric pH was above 3 and 4 when children were dosed with either 15 or 30 mg according to body weight.