Sharon C. Murray

Single‐Dose Pharmacokinetics and Pharmacodynamics of Sergliflozin Etabonate, a Novel Inhibitor of Glucose Reabsorption, in Healthy Volunteers and Patients With Type 2 Diabetes Mellitus

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of sodium‐dependent glucose cotransporter 2 (SGLT2). The pharmacokinetics and pharmacodynamics of sergliflozin were evaluated following single oral dose administration of sergliflozin etabonate (5–500 mg) in healthy volunteers (n = 22) and patients with type 2 diabetes mellitus (n = 8). The prodrug was rapidly and extensively converted to sergliflozin; the latter displayed linear kinetics, reached maximum plasma concentrations at ∼30 to 45 minutes postdose (tmax), and had a plasma elimination half‐life (t1/2) of ∼0.5 to 1 hour. Both prodrug and active entity showed low glomerular filtration and/or extensive renal tubular reabsorption, with <0.5% of the administered dose being recovered in the urine. In both populations, sergliflozin etabonate produced a dose‐related glucosuria under fasting conditions and following glucose loading but did not appreciably affect urinary electrolyte excretion or fluid balance. The magnitude and duration of the glucosuric effect closely paralleled plasma sergliflozin concentrations. Sergliflozin did not significantly affect fasting plasma glucose levels but produced transient attenuation of the plasma glucose AUC following glucose challenge. Single doses of sergliflozin etabonate 5 to 500 mg were well tolerated, and there were no clinically significant adverse laboratory findings.

Perinatal toxicity of maneb, ethylene thiourea, and ethylenebisisothiocyanate sulfide in rodents

The potential of the fungicide maneb and two of its metabolites, ethylenebisisothiocyanate sulfide (EBIS) and ethylene thiourea (ETU), to induce perinatal toxicity in four species of rodents was investigated. The compounds were admininistered to rats and mice during the period of organogenesis, and ETU was also administered to rats and mice during the period of organogenesis, and ETU was also administered by oral gavage for a similar period to hamsters and guinea pigs. Treatment also continued through the lactational period in groups of rats that were allowed to give birth. Fetuses were examined for signs of toxicity, including terata, and neonates for reflex developement and open-field behavior. Maneb produced hydrocephalus in fetuses in litters of rats receiving 480 mg/kg . d. No fetotoxic effects were noted in litters of rats receiving EBIS at doses at high as 30 mg/kg . d. ETU proved to be a potent teratogen in the rat. Among the effects seen at doses of 40 mg/kg . d or greater were hydrocephalus, encephalocele, kyphosis, and various defects of the digits. Neither maneb (up to 1500 mg/kg . d), ETU (up to 200 mg/kg . d), nor EBIS (up to 200 mg/kg . d) elicited signs of fetal toxicity in the mouse. ETU also failed to result in fetal toxicity when administered to the hamster (100 mg/kg . d) or the guinea pig (100 mg/kg . d). Neither maneb nor EBIS produced significant dose-related alterations in the behavioral development of perinatally exposed rat neonates. At doses that also produced neonatal hydrocephalus, ETU produced significant increases in the open-field activity of the neonates. In addition to the perinatal effects noted above, both maneb and EBIS caused maternal limb paralysis in the rat, an effect not noted in the mouse at much higher doses.

Multiple‐Dose Pharmacokinetics and Pharmacodynamics of Sergliflozin Etabonate, a Novel Inhibitor of Glucose Reabsorption, in Healthy Overweight and Obese Subjects: A Randomized Double‐Blind Study

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of the sodium‐dependent glucose cotransporter‐2 in the renal tubule. The pharmacokinetics and pharmacodynamics of sergliflozin were examined during administration of sergliflozin etabonate (500 or 1000 mg) or placebo 3 times daily (tid) for 14 days in healthy overweight or obese human volunteers (n = 18). At the doses tested, sergliflozin showed less than dose‐proportional pharmacokinetic characteristics. Mean half‐life of the active entity was approximately 2 hours; there was no evidence of drug accumulation. Sergliflozin etabonate produced rapid and sustained suppression of renal glucose reabsorption, resulting in a dose‐related glucosuria, and a transient increase in urinary electrolyte and fluid loss; plasma glucose, insulin, and electrolyte levels were unchanged. Sergliflozin etabonate produced a rapid, dose‐related reduction in body weight (mean changes of −0.09, −1.55, and −1.74 kg from baseline to day 15 with placebo, sergliflozin etabonate 500 mg, and sergliflozin etabonate 1000 mg, respectively), apparently through increased urinary calorie loss rather than through osmotic diuresis. Sergliflozin etabonate 500 or 1000 mg tid was generally well tolerated; no clinically significant adverse events were identified. Renal function (creatinine clearance) was not affected by sergliflozin etabonate, although urinary microalbumin, N‐acetyl‐beta‐D‐glucosaminidase, and β2‐microglobulin levels tended to increase.

Single-Dose Safety and Pharmacokinetics of Brecanavir, a Novel Human Immunodeficiency Virus Protease Inhibitor

ABSTRACT Brecanavir (BCV, 640385) is a novel, potent protease inhibitor (PI) with low nanomolar 50% inhibitory concentrations against PI-resistant human immunodeficiency virus (HIV) in vitro. This phase I, double-blind, randomized, placebo-controlled, two-part single-dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of BCV administered at 10 mg/ml in a tocopherol-polyethylene glycol succinate-polyethylene glycol 400-ethanol 50:40:10 solution. In part 1 of the study, single oral doses of BCV ranged from 25 mg to 800 mg. In part 2, single oral doses of BCV ranged from 10 mg to 300 mg and were coadministered with 100-mg oral ritonavir (RTV) soft gel capsules. Single doses of BCV and BCV/RTV were generally well tolerated. There were no severe adverse events (SAEs), and no subject was withdrawn due to BCV. The most commonly reported drug-related AEs during both parts of the study combined were gastrointestinal disturbances (similar to placebo) and headache. BCV was readily absorbed following oral administration with mean times to maximum concentration from >1 h to 2.5 h in part 1 and from 1.5 h to 3 h in part 2. Administration of BCV without RTV resulted in BCV exposures predicted to be insufficient to inhibit PI-resistant virus based on in vitro data. Coadministration of 300 mg BCV with 100 mg RTV, however, significantly increased the plasma BCV area under the concentration-time curve and maximum concentration 26-fold and 11-fold, respectively, achieving BCV concentrations predicted to inhibit PI-resistant HIV.

Chemoimmunotherapy Using Pegylated Liposomal Doxorubicin and Interleukin-18 in Recurrent Ovarian Cancer: A Phase I Dose-Escalation Study

Simpkins and colleagues found that the combination of FDA-approved dose and schedule of pegylated liposomal doxorubicin (PLD) with human recombinant IL-18 (SB-485232) in patients with recurrent advanced ovarian cancer induced minimal toxicity across the IL-18 dose range studied and did not reach a maximum tolerated dose. The concomitant and repeat administration of PLD did not attenuate the immunostimulatory effects of IL-18, providing a rationale for a future phase II trial to further evaluate this combination regimen. Recombinant interleukin (IL)-18 (SB-485232) is an immunostimulatory cytokine, with shown antitumor activity in combination with pegylated liposomal doxorubicin (PLD) in preclinical models. This phase I study evaluated the safety, tolerability, and biologic activity of SB-485232 administered in combination with PLD in subjects with recurrent ovarian cancer. The protocol comprised four cycles of PLD (40 mg/m2) on day 1 every 28 days, in combination with SB-485232 at increasing doses (1, 3, 10, 30, and 100 μg/kg) on days 2 and 9 of each cycle, to be administered over five subject cohorts, followed by discretionary PLD monotherapy. Sixteen subjects were enrolled. One subject withdrew due to PLD hypersensitivity. Most subjects (82%) were platinum-resistant or refractory, and had received a median of three or more prior chemotherapy regimens. SB-485232 up to 100 μg/kg with PLD had an acceptable safety profile. Common drug-related adverse events were grade 1 or 2 (no grade 4 or 5 adverse events). Concomitant PLD administration did not attenuate the biologic activity of IL-18, with maximal SB-485232 biologic activity already observed at 3 μg/kg. Ten of 16 enrolled subjects (63%) completed treatment, whereas five (31%) subjects progressed on treatment. A 6% partial objective response rate and a 38% stable disease rate were observed. We provide pilot data suggesting that SB-485232 at the 3 μg/kg dose level in combination with PLD is safe and biologically active. This combination warrants further study in a phase II trial. Cancer Immunol Res; 1(3); 168–78. ©2013 AACR.

Sample Size Calculations for Crossover Thorough QT Studies: Satisfaction of Regulatory Threshold and Assay Sensitivity

The cost for conducting a “thorough QT/QTc study” is substantial and an unsuccessful outcome of the study can be detrimental to the safety profile of the drug, so sample size calculations play a very important role in ensuring adequate power for a thorough QT study. Current literature offers some help in designing such studies, but these methods have limitations and mostly apply only in the context of linear mixed models with compound symmetry covariance structure. It is not evident that such models can satisfactorily be employed to represent all kinds of QTc data, and the existing literature inadequately addresses whether there is a change in sample size and power for more general covariance structures for the linear mixed models. We assess the use of some of the existing methods to design a thorough QT study through data arising from a GlaxoSmithKline (GSK)-conducted thorough QT study, and explore newer models for sample size calculation. We also provide a new method to calculate the sample size required to detect assay sensitivity with adequate power.

Safety and Pharmacokinetics of Brecanavir, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor, following Repeat Administration with and without Ritonavir in Healthy Adult Subjects

ABSTRACT Brecanavir (BCV) is a novel, potent protease inhibitor in development for the treatment of human immunodeficiency virus (HIV-1) infection with low nM in vitro 50% inhibitory concentrations (IC50s) against many multiprotease inhibitor resistant viruses. This study was a double-blind, randomized, placebo-controlled repeat-dose escalation to evaluate the safety, tolerability, and pharmacokinetics of BCV, with or without ritonavir (RTV), in 68 healthy subjects. Seven sequential cohorts (n = 10) received BCV (50 to 600 mg) in combination with 100 mg RTV (every 12 h [q12h] or q24h) or alone at 800 mg q12h for 15 days. BCV alone or in combination with RTV was well tolerated, with no serious adverse events reported. The most common drug-related adverse event was headache. BCV was readily absorbed with median time to maximum concentration of drug in serum values ranging from 2.5 to 5.0 h postdose following single- and repeat-dose administration of BCV alone and BCV with RTV 100 mg. Geometric mean BCV accumulation ratios ranged from 1.4 to 1.56 following BCV-RTV q24h regimens and from 1.84 to 4.93 following BCV q12h regimens. BCV steady state was generally achieved by day 13 in all groups. All day 15 BCV-RTV trough concentration values in q12h regimens reached or surpassed the estimated protein-binding corrected in vitro IC50 target BCV concentration of 28 ng/ml for highly resistant isolates. The pharmacokinetic and safety profile of BCV-RTV supports continued investigation in HIV-1-infected subjects.

Effect of Casopitant, a Novel NK‐1 Receptor Antagonist, on the Pharmacokinetics and Pharmacodynamics of Steady‐State Warfarin

Casopitant, a novel NK‐1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy‐induced nausea and vomiting, is a weak to moderate inhibitor of CYP3A and a moderate inducer of CYP2C9 in vitro. Furthermore, both CYP enzymes are involved in the metabolism of R‐ and S‐warfarin, respectively. This clinical study was conducted to explore the potential drug—drug interaction between casopitant and warfarin. In total, 97 healthy participants were enrolled and 54 completed the study. Participants received individualized daily dosing of warfarin to an international normalized ratio (INR) of 1.3 to 2.3 over a 14‐day period (period 1). Immediately following period 1, participants entered period 2 and were randomized to receive either regimen A (oral casopitant [150 mg day 1, 50 mg days 2 and 3] and warfarin [days 1–10]) or regimen B (oral casopitant 60 mg and warfarin [days 1–14]). INR assessments were performed daily. The steady‐state Cmax and AUC of R‐ and S‐warfarin were not altered by regimen A, but R‐warfarin AUC was increased 1.31‐fold (90% confidence interval [CI]: 1.22, 1.41), and S‐warfarin AUC was increased 1.27‐fold (90% CI: 1.18, 1.38) on day 14 in regimen B. Steady‐state INR values were not affected by either casopitant regimen.

Abstract C132: Effect of hepatic or renal impairment on the pharmacokinetics of casopitant

Introduction: The pharmacokinetics and safety of casopitant, a neurokinin‐1 receptor antagonist being developed for the prevention of chemotherapy‐induced and post‐operative nausea and vomiting, were evaluated in subjects with mild (Child‐Pugh score of 5–6) and moderate (Child‐Pugh score of 7–9) hepatic impairment; mild (creatinine clearance 50–80 mL/min) and moderate (creatinine clearance 30–49 mL/min) renal impairment; and subjects with normal hepatic and renal function. Experimental Design: Twenty‐six subjects were enrolled in the hepatic impairment study (9 mild, 9 moderate and 8 normal subjects) and 18 subjects in the renal impairment study (6 mild, 6 moderate and 6 normal subjects). Subjects with severe hepatic or renal impairment were excluded. All subjects received a once‐daily dose of 100 mg oral casopitant for 5 days. Pharmacokinetics and plasma protein binding of casopitant and its major metabolite, GSK525060, were determined on Days 1 and 5. Safety was continuously assessed. Results: Subjects with mild or moderate hepatic impairment had an increase in casopitant AUC of 11% and 24%, respectively, on Day 1 compared with normal subjects; a similar increase was observed on Day 5. Casopitant Cmax was variable, but similar across all subjects. GSK525060 AUC was not significantly different between normal subjects and subjects with mild hepatic impairment; however, AUC was reduced 29% and 19% on Days 1 and 5, respectively, in subjects with moderate hepatic impairment. The percent bound of casopitant and GSK525060 was similar in all subjects. Casopitant AUC increased 34% and 22% in subjects with mild or moderate renal impairment on Day 1, respectively, and 28% and 11% on Day 5, respectively, when compared with normal subjects. GSK525060 AUC increased 17% and 24% on Days 1 and 5, respectively, in subjects with mild renal impairment, but did not significantly change in subjects with moderate impairment. Further age‐adjusted analysis showed no meaningful effect of renal impairment on casopitant or GSK525060 AUC. Cmax and half‐life in renal impaired subjects were similar to normal subjects. The plasma protein‐binding of casopitant and GSK525060 was similar in all subjects. Casopitant was well tolerated, with no significant difference in the type or frequency of adverse events (AEs) noted between subjects with mild, moderate or no hepatic or renal impairment. Somnolence, flatulence and nausea were the most frequently reported AEs in the hepatic impairment study; whereas constipation and dyspepsia were the most frequently reported events in the renal impairment study. No AEs were reported in subjects with mild renal impairment. Conclusion: The pharmacokinetics of casopitant is not altered to a clinically significant extent in subjects with mild or moderate, hepatic or renal impairment. The impact of severe hepatic or renal impairment on the pharmacokinetics and safety of casopitant was not evaluated. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C132.