Bioavailability Section
Bioequivalence study of a new oral topotecan formulation, relative to the current topotecan formulation, in patients with advanced solid tumors
R.L. Oostendorp, J. Loftiss, S. Goel, D.A. Smith, M.M. Dar, P.O. Witteveen, R.B. Cohen, L.D. Lewis, S. Kurian, A. Patnaik, H. Rosing, J.H. Beijnen, E.E. Voest, H. Burris and J.H.M. Schellens
Price
42.00 $
Volume 47 p. 195 - 206
Abstract
R.L. Oostendorp1, J. Loftiss2, S. Goel3, D.A. Smith2, M.M. Dar2, P.O. Witteveen4, R.B. Cohen5, L.D. Lewis6, S. Kurian7, A. Patnaik8, H. Rosing9, J.H. Beijnen9,10, E.E. Voest4, H. Burris11 and J.H.M. Schellens1,10
1Department of Medical Oncology, The Netherlands Cancer Institute, The Netherlands, 2GlaxoSmithKline, Research Triangle Park, NC, USA, 3Montefiore Medical Center Bronx, NY, USA, 4Department of Medical Oncology, University Medical Center Utrecht, The Netherlands, 5Fox Chase Cancer Center Philadelphia, PA, USA, 6Dartmouth Medical School and Dartmouth-Hitchcock Medical Center Lebanon, NH, USA, 7Mary Babb Randolph Cancer Center Morgantown, WV, USA, 8Cancer Therapy and Research Center San Antonio, TX, USA, 9Department of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands, 10Faculty of Science, Department of Pharmaceutical Sciences, Division of Biomedical Analysis, University Utrecht, The Netherlands, and 11Sarah Cannon Research Institute Nashville, TN, USA
Objective: The aims of this study were to investigate the bioequivalence of a new oral topotecan formulation (i.e., proposed commercial formulation) relative to the current oral formulation (formulation used in previous clinical trials), the effect of food on the absorption and disposition of the new oral topotecan and its safety and tolerability in patients with advanced solid tumors. Patients and methods: This was a multi-center, pharmacological Phase I, multiple-dose, randomized, open-label, cross-over bioequivalence study. In the bioequivalence part, 85 patients were randomized to receive either a 4 mg (4 × 1 mg) dose of the new or current formulation on Days 1 or 8. In the food-effect part, 23 patients received a 4 mg (4 × 1 mg) dose of the new formulation in a fasted and fed state. Total topotecan and topotecan lactone were determined and pharmacokinetic data were analyzed by non-compartmental method. Results: Bioequivalence was demonstrated as the 90% confidence intervals of the ratio of the new to current formulation for both the area under the plasma concentration-time curve (AUC) and the maximal drug concentration (Cmax) for topotecan lactone were contained within the 0.8 – 1.25 boundary. The AUC and Cmax were similar in the fed and fasted state whilst food delayed the tmax for topotecan lactone and total topotecan. Safety data were collected on all subjects enrolled (n = 108) and were consistent with observations from previous studies of oral topotecan. All subjects experienced at least one adverse event, the majority of which were graded as mild to moderate in severity. Conclusion: The new oral topotecan formulation demonstrated bioequivalence to the current formulation and demonstrated it can be administered to patients with solid tumors in the fed or fasted state with similar systemic exposure.Correspondence to:
R.L. Oostendorp, MSc; The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
Email: [email protected]
Original Research
Pharmacokinetic comparisons of three nasal fentanyl formulations; pectin, chitosan and chitosan-poloxamer 188
A. Fisher, M. Watling, A. Smith and A. Knight
Price
42.00 $
Volume 48 p. 138 - 145
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 2/2010 (138-145)
Pharmacokinetic comparisons of three nasal fentanyl formulations; pectin, chitosan and chitosan-poloxamer 188
A. Fisher1, M. Watling1, A. Smith1 and A. Knight2
1Archimedes Development Limited, Albert Einstein Centre, Nottingham Science and Technology Park, University Boulevard, Nottingham, and 2Evicom Limited, Somerset House, Teddington, UK
Objectives: To optimize the absorption profile and reduce Cmax, three new fentanyl nasal spray formulations have been developed: fentanyl pectin (FPNS), fentanyl chitosan (FChNS) and fentanyl in chitosan-poloxamer 188 (FChPNS). The venous pharmacokinetic profiles and tolerability of these formulations were assessed and compared with oral transmucosal fentanyl citrate (OTFC) lozenge. Subjects and methods: This randomized, open-label, crossover study was conducted in opioid-naïve, healthy adult volunteers. Subjects were dosed under naltrexone blockade on four occasions with three nasal sprays (100 µg in 100 µl) and OTFC 200 µg. Fentanyl venous plasma concentrations were measured up to 24 h post-dose. Tolerability was assessed by clinical nasal assessments and a nasal reactogenicity questionnaire. Results: 18 subjects were enrolled and completed the study. The mean dose-normalized AUC0-∞ for each nasal formulation was significantly higher (p < 0.05) compared with OTFC. Bioavailability compared with OTFC was significantly greater for all nasal fentanyl formulations (FPNS 132.4%, FChNS 154.1%, FChPNS 122.3%). Median tmax (FPNS 0.33 h, FChNS 0.17 h, FChPNS 0.26 h) were significantly (p < 0.001) reduced (OTFC 1.5 h) and mean Cmax significantly increased with all nasal formulations compared with OTFC. Nasal reactogenicity symptom incidence was lowest for the FPNS formulation (FPNS 2, FChNS 28 and FChPNS 45). Conclusions: All nasal formulations demonstrated significantly increased systemic exposure and reduced times to peak plasma values compared with OTFC. The FPNS formulation exhibited the most favorable nasal and general tolerability profiles. It appears suitable for further investigation in breakthrough cancer pain management.Correspondence to:
A. Fisher, PhD
Archimedes Development Limited
Albert Einstein Center
Nottingham Science and Technology Park
University Boulevard
Nottingham, NG7 2TN, UK
Email: [email protected]
Bioavailability Section
Pharmacokinetics and relative bioavailability of fentanyl pectin nasal spray 100 – 800 µg in healthy volunteers
A. Fisher, M. Watling, A. Smith and A. Knight
Price
42.00 $
Volume 48 p. 860 - 867
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 12/2010 (860-867)
Pharmacokinetics and relative bioavailability of fentanyl pectin nasal spray 100 – 800 µg in healthy volunteers
A. Fisher1, M. Watling1, A. Smith1 and A. Knight2
1Archimedes Development Limited, Albert Einstein Centre, Nottingham Science and Technology Park, University Boulevard, Nottingham, and 2Evicom Limited, Somerset House, Teddington, UK
Objectives: Fentanyl pectin nasal spray (FPNS) is formulated as a solution utilizing PecSys®; pectin based enabling technology (Archimedes). On contact with the nasal mucosa the formulation will gel and modulate fentanyl absorption while limiting nasal drip or runoff. This single-dose volunteer study compared the pharmacokinetics of FPNS 100, 200, 400, and 800 µg doses and assessed bioavailability relative to oral transmucosal fentanyl (OTFC) 200 µg. Safety and dose proportionality were also examined. Subjects and methods: 16, opioid-naïve subjects were dosed on five separate visits under naltrexone block. FPNS doses were administered using a Pfeiffer device delivering 100 µl. Devices were filled with either 1.57 mg/ml (100 and 200 µg dosing) or 6.28 mg/ml fentanyl citrate (400 and 800 µg). Venous blood samples were collected up to 48 h after dosing and plasma fentanyl concentrations measured. Results: Median tmax values for FPNS ranged from 15 to 21 min post-dose and were dose-independent. At 200 µg Cmax values were 2.3-fold higher for FPNS compared with OTFC. Mean relative bioavailability of FPNS to OTFC ranged from 103% to 163%. Dose proportionality for Cmax and AUC0–1 across the FPNS range was statistically confirmed. Drug absorption also increased in a close to dose-proportional manner for AUC0–inf. Conclusions: FPNS has a shorter tmax, higher Cmax and greater bioavailability than OTFC and is well tolerated. The dose proportionality of Cmax and AUC0–1 was demonstrated. It is concluded that the pharmacokinetic profile of FPNS suggests this product is suitable for clinical investigation in breakthrough pain in cancer patients.Correspondence to:
A. Fisher, PhD
Archimedes Development Limited
Albert Einstein Centre
Nottingham Science and Technology Park
University Boulevard, Nottingham, NG7 2TN, UK
Email: [email protected]
Case Report
Peramivir pharmacokinetics in a patient receiving continuous veno-venous hemodiafiltration during the 2009 H1N1 influenza A pandemic
Michael L. Bentley, Alan S. Hollister, Amanda C. Hansen, Jean A. Smith, and James S. Cain
Price
42.00 $
Volume 52 p. 1105 - 1111
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 12/2014 (1105-1111)
Peramivir pharmacokinetics in a patient receiving continuous veno-venous hemodiafiltration during the 2009 H1N1 influenza A pandemic
Michael L. Bentley1,2, Alan S. Hollister3a, Amanda C. Hansen4b, Jean A. Smith2,5, and James S. Cain2,6
1Department of Pharmacy, Carilion Clinic, 2Virginia Tech Carilion School of Medicine (VTCSOM), Roanoke, VA, 3Clinical Pharmacology Consulting LLC, Durham, NC, 4Department of Pharmacy, The Cleveland Clinic, Cleveland, OH, 5Department of Internal Medicine, Division of Infectious Disease, Carilion Clinic, and 6Valley Nephrology Associates, Roanoke, VA, USA
Objective: Peramivir is a neuraminidase inhibitor having activity against various influenza A and B subtypes. The main route of elimination is the kidney and a dose reduction is justified for multipleday therapy when the creatinine clearance is < 50 mL/min. Before the 2009 influenza pandemic, dosing guidelines did not exist for patients receiving continuous renal replacement therapy (CRRT). This case report provides data on the dialysis membrane saturation coefficient (SA) and pharmacokinetic parameters of peramivir in a 29-year-old female receiving continuous veno-venous hemodiafiltration (CVVHDF), a mode of CRRT. Methods: Plasma and effluent samples were collected to calculate the saturation coefficient, plasma half-life, maximum and minimum plasma concentrations, and area under the plasma drug concentrationtime curve (AUC) for peramivir. CVVHDF was performed using a Prisma pump and an AN69 filter. During peramivir sampling, the dialysate flow rate was 16.7 mL/min. The mean total ultrafiltrate produced was 14.2 mL/min. To calculate a saturation coefficient (SA), simultaneous sampling of blood and effluent was performed. Pre- and post-filter as well as effluent samples were obtained 4.5 and 8.5 hours following the 3rd dose of 480 mg. Plasma concentrations were also obtained at several time points and the AUC estimated from 0 to 24 hours (AUC0– 24). Results: The maximum plasma concentration (C30min) was 19,477 ng/mL, the minimum plasma concentration (Cmin) 2,750 ng/mL, and AUC0–24 196,166 ng×h/mL. The estimated plasma half-life was 8.2 hours with a log-linear decrease over the 24-hour period suggesting significant extracorporeal clearance. The calculated SA was 0.98, similar to an estimated SA of 1. Conclusion: Peramivir is readily cleared by CVVHDF having a calculated SA close to 1. The maximum and minimum plasma concentrations, AUC0–24, and plasma half-life was similar to those previously reported. These data will be useful in determining appropriate peramivir dosing regimens for severely ill influenza patients with acute renal impairment managed by CVVHDF.Correspondence to:
Michael L. Bentley, PharmD, FCCP, FCCM, FNAP
Department of Pharmacy
1960 Belleview Ave l 14th Floor, Roanoke, VA 24014, USA
Email: mlbentley@carilion clinic.org
Original Research
Effects of a novel sodium channel blocker, GSK2339345, in patients with refractory chronic cough
Jaclyn A. Smith, Lorcan P.A. McGarvey, Huda Badri, Imran Satia, Francis Warren, Sarah Siederer, Lia Liefaard, Robert D. Murdoch, Kathryn Povey, and Joanna Marks-Konczalik
Price
42.00 $
Volume 55 (2017) p. 712 - 719
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 9/2017 (712-719)
Effects of a novel sodium channel blocker, GSK2339345, in patients with refractory chronic cough
Jaclyn A. Smith1,2, Lorcan P.A. McGarvey3, Huda Badri1,2, Imran Satia1,2, Francis Warren4, Sarah Siederer5, Lia Liefaard5, Robert D. Murdoch5, Kathryn Povey4, and Joanna Marks-Konczalik5
1Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, and Manchester Academic Health Science Centre, The University of Manchester, 2University Hospital of South Manchester, Manchester, 3Centre for Experimental Medicine, Queen’s University Belfast, Belfast, 4GlaxoSmithKline R&D, Stockley Park West, Uxbridge, Middlesex, and 5GlaxoSmithKline R&D, Stevenage, UK
Objective: Voltage-gated sodium channels (VGSC) are important in the initiation and propagation of action potentials in afferent sensory nerve fibers responsible for evoking cough. This study investigated the efficacy of GSK2339345, a VGSC inhibitor, in the treatment of refractory chronic cough (RCC). Methods: A three-part randomized, double-blind, placebo-controlled, cross-over study was conducted in the UK. In part A, patients with RCC received two inhaled doses of either GSK2339345 or placebo, 4 hours apart during three study periods. Patients were monitored for cough for 8 hours post-first dose using the VitaloJAK, ambulatory cough monitor. In parts B and C, patients underwent full dose-response cough challenges with capsaicin and citric acid respectively following single doses of randomly assigned GSK2339345 or placebo (4 study days). Part A was analyzed using a mixed effects model and parts B and C using population non-linear mixed effects models. Results: Of 16 enrolled patients, 11 completed the study. 8-hour cough counts increased following GSK2339345 treatment compared with placebo (GSK2339345/placebo ratio of adjusted geometric means: 1.26 (90% credible interval 1.10, 1.44), associated with GSK2339345-evoked coughing, recorded during the 2 minutes post-dose. This was not observed with placebo. The effect of GSK2339345 on cough responses during cough challenges was inconclusive. GSK2339345 was well tolerated. Conclusions: While these data could not determine if GSK2339345 reached the target VGSC, they strongly suggest that GSK2339345 has no anti-tussive effect despite reaching airway sensory nerves as evidenced by the evoked transient cough.
Correspondence to:
Prof. Jaclyn A. Smith, MB, ChB, PhD, FRCP
Education and Research Centre, 2nd Floor
University Hospital of South Manchester
Southmoor Rd, M23 9LT Manchester, UK
Email: jacky.smith@manchester.ac.uk
