David Lau

Pharmacokinetics of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in healthy human subjects following single and multiple oral dosing in three phase I studies.

AIM Fostamatinib (R788) is an orally dosed prodrug designed to deliver the active metabolite R940406 (R406), a spleen tyrosine kinase (SYK) inhibitor, for the treatment of rheumatoid arthritis. The objectives were to evaluate the human pharmacokinetic properties of fostamatinib and R406. METHOD Three clinical studies were conducted in healthy subjects: (A) A single ascending dose study for R406 with doses ranging from 80-600 mg, (B) a single- and multiple-dose study of fostamatinib in aqueous suspension, with single doses ranging from 80-400 mg and multiple doses at 160 mg twice daily and (C) a study comparing suspension and tablet of fostamatinib, with the latter tested in both fed and fasted states. RESULTS These studies demonstrated that when administered as a solution, R406 was rapidly absorbed. Increases in exposure were observed with doses up to 400 mg. A terminal half-life of 12-21 h was observed. Similar R406 exposure could be achieved with fostamatinib suspension and steady-state was achieved after 3-4 days following twice daily administration. Fostamatinib tablet and suspension exhibited similar R406 exposure. Upon co-administration with food, a delay in peak time and lower peak concentrations of R406 were observed but at the same time the overall exposure did not change. CONCLUSION Fostamatinib demonstrates rapid and extensive conversion to R406, an inhibitor of SYK. Solid dosage forms of fostamatinib overcome the challenge of low aqueous solubility of R406. The PK profile of R406 could potentially allow once daily or twice daily oral administration of fostamatinib.

Pharmacokinetics of Dexamethasone Solution following Intratympanic Injection in Guinea Pig and Sheep

Information on inner ear pharmacokinetics is limited in the literature, especially in large animals and in humans. A preliminary study was designed to explore the differences in inner ear exposure between guinea pigs and sheep following a single intratympanic injection of a 2% dexamethasone sodium phosphate solution. In both species, significant levels of dexamethasone were observed in the perilymph within 1 h, and decreasing by 50- to 100-fold within 12 h. Overall, the exposure to dexamethasone in the inner ear was significantly lower in sheep by 17- to 27-fold than in guinea pigs. Systemic and CNS exposure were minimal in both species as indicated by the low drug levels observed in plasma and CSF. Altogether, the preliminary evidence presented herein suggests the sheep as a practical and acceptable animal model to study the inner ear pharmacokinetics of drug candidates in large mammals and its potential towards extrapolation to human exposure.

Fostamatinib, a Syk-Kinase Inhibitor, Does Not Affect Methotrexate Pharmacokinetics in Patients With Rheumatoid Arthritis

Fostamatinib (R788) is being investigated as an add‐on therapy for the treatment of rheumatoid arthritis (RA) in patients with inadequate response to methotrexate (MTX). This study evaluated the potential pharmacokinetic interaction between R788 and MTX. Sixteen RA subjects on a stable weekly MTX regimen were enrolled and received MTX on days 1 and 8. Twelve subjects received 100 mg of R788 orally, and 4 subjects received a matching placebo twice daily from days 4 to 8 and once daily on days 3 and 9. Blood samples were collected on days 1 and 8 for MTX and 7‐hydroxymethotrexate (7‐OH‐MTX), and days 3 and 9 for R788 and its active metabolite, R406. MTX and 7‐OH‐MTX pharmacokinetic parameters were similar on days 1 and 8. In the R788 group, the mean day 8 to day 1 ratios (90% confidence intervals) of maximum concentration and area under the plasma concentration—time curve estimates were 1.01 (0.85–1.20) and 1.12 (0.90–1.40) for MTX and 1.06 (0.82–1.35) and 1.06 (0.83–1.36) for 7‐OH‐MTX, respectively. Urinary excretion of MTX and 7‐OH‐MTX was also similar with or without R788, averaging 58% to 69% and 4% to 5% of the MTX dose, respectively. The data suggest that there is no clinically significant pharmacokinetic interaction of R788 and MTX in RA patients.

Pharmacokinetics and Pharmacodynamics of a Novel Depot Formulation of Abarelix, a Gonadotropin‐Releasing Hormone (GnRH) Antagonist, in Healthy Men Ages 50 to 75

This study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel depot formulation of abarelix, a new gonadotropin‐releasing hormone (GnRH) antagonist. This was an open‐label, sequential two‐phase study in healthy male subjects ages 50 to 75. Subjects received a single intramuscular (IM) dose of 15 μg/kg abarelix injectable solution, followed by a 21‐day washout period and a subsequent intramuscular dose of 100 mg abarelix depot. The PK and the hormonal suppression effects of abarelix were evaluated based on testosterone (T), dihydrotestosterone (DHT), follicle‐stimulating hormone (FSH), and luteinizing hormone (LH) levels. Abarelix provides immediate competitive blocking of the GnRH receptors on pituitary gonadotropes without causing release of gonadotropins, and these effects are reversible. The mean IC50s of abarelix for T, DHT, FSH, and LH were 2.08, 3.42, 6.43, 4.25 ng/mL, respectively. The mean relative bioavailability of the depot formulation in reference to the injectable solution was 0.52. The mean tmax and terminal t1/2 for abarelix after administration of abarelix injectable solution and abarelix depot injection were 1 hour and 3 days and 0.22 days (5.3 h) and 13.2 days, respectively. The novel abarelix depot formulation used in this study significantly improved the duration of abarelix delivery and pharmacological activities compared to the injectable formulation, without causing any safety issues.

Pharmacokinetics and pharmacodynamics of abarelix, a gonadotropin-releasing hormone antagonist, after subcutaneous continuous infusion in patients with prostate cancer

Our objective was to evaluate the pharmacokinetic and pharmacodynamic characteristics of abarelix after continuous subcutaneous infusion of 50 μg · kg−1 · d−1 in patients with prostate cancer and to identify a plasma concentration of abarelix that may provide a sustained pharmacodynamic effect.

Pharmaceutical Significance of the Cyclic Imide Form of Recombinant Human Glial Cell Line Derived Neurotrophic Factor

AbstractPurpose. The purpose of this paper is to determine the significance of cyclic imide formation of an aspartic acid residue during storage on the pharmaceutical quality of a recombinant human glial cell line-derived neurotrophic factor (rhGDNF) formulation. Methods. A combination of chromatography, peptide mapping, mass spectroscopy, and protein sequencing was used to purify and characterize the degradation product. Circular dichroism, 1,8-ANS and heparin binding, melting temperature determination, bioassays, and preclinical pharmacokinetic and toxicology testing were performed to examine its equivalence to native rhGDNF.Results. The rhGDNF with cyclic imide at aspartic acid residue 96 showed identical activity, structure, pharmacokinetic profile, and toxicity profile to the native rhGDNF. Conclusions. Formation of cyclic imide at aspartic acid residue 96 does not affect the pharmaceutical quality of the rhGDNF formulation.

Effects of Fostamatinib on the Pharmacokinetics of Digoxin (a P-Glycoprotein Substrate): Results From in Vitro and Phase I Clinical Studies

PURPOSE Fostamatinib, a spleen tyrosine kinase inhibitor and prodrug of the active metabolite R406, is being developed as an anti-inflammatory drug for several indications for which polypharmacy is likely. Digoxin, indicated for congestive cardiac failure, may be used for certain supraventricular dysrhythmias. The studies reported herein examined whether fostamatinib and R406 are inhibitors of P-glycoprotein (P-gp) in vitro and evaluated the effect of fostamatinib on the pharmacokinetic parameters of digoxin to understand drug-drug interaction (DDI) potential in the clinic. METHODS Inhibition of P-gp-mediated digoxin transport by fostamatinib and R406 was determined across Caco-2 cell monolayers. Apparent permeability of digoxin was determined and used to calculate efflux ratios and percentage inhibition. Half maximal inhibitory concentrations (IC50) and theoretical gastrointestinal concentration [I2] (dose in moles per 250 mL) were calculated to gauge clinical DDI potential. In a subsequent Phase I study, the plasma concentration-time profiles and resulting pharmacokinetic parameters were examined across 2 treatment periods: (1) oral digoxin loading dose of 0.25 mg BID on day 1 and 0.25 mg once daily on days 2 to 8, and (2) oral digoxin 0.25 mg once daily and oral fostamatinib 100 mg BID on days 9 to 15. FINDINGS Fostamatinib (but not R406) was determined to be a P-gp inhibitor in vitro (IC50 = 3.2 μM). On the basis of a theoretical gastrointestinal concentration (I2)/IC50 ratio of 216 ([I2] = 691 μM), predictions indicated the potential for absorption-based DDI in vivo through inhibition of intestinal P-gp. In the clinical study, when digoxin was co-administered with fostamatinib, digoxin levels were higher before dosing and throughout the dosing interval, and an increase in exposure to digoxin was observed. Co-administration led to a 1.70-fold increase in digoxin maximum plasma concentration at steady state (Cmax,ss) versus digoxin administration alone (2.18 vs 1.32 ng/mL). Median digoxin time of Cmax was earlier when digoxin was co-administered with fostamatinib (1.00 vs 1.48 hours). The digoxin AUC during the dosing interval at steady state was increased 1.37-fold with co-administration. No severe or serious adverse events or deaths were reported. IMPLICATIONS Fostamatinib was confirmed to be a P-gp inhibitor in vitro and in vivo, and a DDI with digoxin was apparent. Co-administration of digoxin and fostamatinib was generally well tolerated. However, continued review of digoxin response and dose is advisable should these agents be prescribed concomitantly. ClinicalTrials.gov identifier: NCT01355354.

Effects of Fostamatinib on the Pharmacokinetics of the CYP2C8 Substrate Pioglitazone: Results From In Vitro and Phase 1 Clinical Studies.

Fostamatinib is a prodrug that undergoes gastrointestinal tract dephosphorylation to form the active metabolite, R406. Here we report its cytochrome P450–inducing potential. In vitro, R406 3 and 10 μM induced CYP2C8 to levels representing 53% and 75%, respectively, of the level achieved by the positive control, rifampicin. Induction of other enzymes was minor. The effect of fostamatinib (100 mg twice daily) on the pharmacokinetics of a single oral 30‐mg dose of the CYP2C8 substrate pioglitazone and its metabolite, hydroxy pioglitazone, was then investigated (open‐label, nonrandomized, 2‐period phase I study [n = 15]). Coadministration of fostamatinib and pioglitazone (vs pioglitazone alone) was associated with lower mean maximum plasma concentration values for pioglitazone (geometric least‐squares mean ratio, 82.8; 90% confidence interval, 64.2–106.8) and hydroxy pioglitazone (90.9; 78.6–105.1), an increase in pioglitazone AUC (117.8; 108.4–128.0), a decrease in hydroxy pioglitazone AUC(0–t) (89.7; 78.9–101.9), and an increase in pioglitazone geometric mean t1/2λz (9.4–12.8 hours). No tolerability concerns were identified upon coadministration. These data suggest that although clinical significance has not been formally evaluated, fostamatinib is unlikely to have a clinically significant effect on the pharmacokinetics of pioglitazone (which may be extrapolated to other CYP2C8 substrates). However, vigilance is advised should these agents be prescribed together.