Nishit B. Modi
Genentech
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Circulation | 1997
Christopher P. Cannon; Carolyn H. McCabe; Cm Gibson; Magdi Ghali; Rafael Sequeira; George R. McKendall; Breed J; Nishit B. Modi; Nl Fox; Russell P. Tracy; Love Tw; Eugene Braunwald
BACKGROUND TNK-tissue plasminogen activator (TNK-TPA) is a genetically engineered variant of TPA, which in experimental models has a slower plasma clearance and greater fibrin specificity and is 80-fold more resistant to plasminogen activator inhibitor-1 than alteplase TPA. METHODS AND RESULTS The thrombolysis in Myocardial Infarction (TIMI) 10A trial was a Phase 1, dose-ranging pilot trial designed to evaluate the pharmacokinetics, safety, and efficacy of TNK-TPA in patients with acute myocardial infarction. One hundred thirteen patients with acute ST-segment elevation myocardial infarction presenting within 12 hours and without contraindications to thrombolysis were enrolled and treated with a single bolus of TNK-TPA over 5 to 10 seconds with doses ranging from 5 to 50 mg. TNK-TPA demonstrated a plasma clearance of 151 +/- 55 mL/min and a half-life of 17 +/- 7 minutes. Comparable values for wild-type TPA are 572 +/- 132 mL/min and 3.5 +/- 1.4 minutes, respectively. Systemic fibrinogen and plasminogen levels fell by only 3% and 13%, respectively, at 1 hour after TNK-TPA administration. TIMI grade 3 flow at 90 minutes was achieved in 57% to 64% of patients at the 30- to 50-mg doses. Seven patients (6.2%) experienced a major hemorrhage, which occurred at a vascular access site in six patients. CONCLUSIONS TNK-TPA has a prolonged half-life so it can be administered as a single bolus. TNK-TPA appears to be very fibrin specific, and the initial patency and safety profiles are encouraging. Further study of this new thrombolytic agent is ongoing.
Clinical Pharmacokinectics | 2002
Paul Tanswell; Nishit B. Modi; Dan Combs; Thierry Danays
Tenecteplase is a novel fibrinolytic protein bioengineered from human tissue plasminogen activator (alteplase) for the therapy of acute ST-segment elevation myocardial infarction. Specific mutations at three sites in the alteplase molecule result in 15-fold higher fibrin specificity, 80-fold reduced binding affinity to the physiological plasminogen activator inhibitor PAI-1 and 6-fold prolonged plasma half-life (22 vs 3.5 minutes). Consequently, tenecteplase can be administered as a single intravenous bolus of 30–50mg (0.53 mg/kg bodyweight) over 5–10 seconds, in contrast to the 90-minute accelerated infusion regimen of alteplase.Tenecteplase plasma concentration-time profiles have been obtained from a total of 179 patients with acute myocardial infarction. Tenecteplase exhibited biphasic disposition; the initial disposition phase was predominant with a mean half-life of 17–24 minutes, and the mean terminal half-life was 65–132 min. Over the clinically relevant dose range of 30–50mg, mean clearance (CL) was 105 ml/min. The mean initial volume of distribution V1 was 4.2–6.3L, approximating plasma volume, and volume of distribution at steady state was 6.1–9.9L, suggesting limited extravascular distribution or binding. Bodyweight and age were found to influence significantly both CL and V1. Total bodyweight explained 19% of the variability in CL and 11% of the variability in V1, and a 10kg increase in total bodyweight resulted in a 9.6 ml/min increase in CL. This relationship aided the development of a rationale for the weight-adjusted dose regimen for tenecteplase. Age explained only a further 11% of the variability in CL.The percentage of patients who achieved normal coronary blood flow was clearly related to AUC. More than 75% of patients achieved normal flow at 90 minutes after administration when their partial AUC2–90 exceeded 320 μg · min/ml, corresponding to an average plasma concentration of 3.6 μg/ml. Systemic exposure to tenecteplase at all times after bolus administration of 30–50mg was higher than for alteplase 100mg.Tenecteplase has demonstrated equivalent efficacy and improved safety compared with the current gold standard alteplase in a large mortality trial (ASSENT-2). This suggests that the reduced clearance, greater fibrin specificity and higher PAI-1 resistance of tenecteplase allow higher plasma concentrations and thus a more rapid restoration of coronary patency to be attained, while providing a reduction in major non-cerebral bleeding events.
The Journal of Clinical Pharmacology | 2000
Nishit B. Modi; Nl Fox; Fong-Wong Clow; Paul Tanswell; Christopher P. Cannon; Frans Van de Werf; Eugene Braunwald
Tenecteplase is a site‐specific engineered tissue plasminogen activator (t‐PA) variant that can be administered as a single intravenous bolus injection because of its slower plasma clearance. The objective of this study was to investigate the dose‐ranging pharmacokinetics and pharmacodynamics of intravenous bolus tenecteplase compared with intravenous alteplase recombinant t‐PA in patients with acute myocardial infarction. A total of 103 patients received intravenous bolus doses of 30, 40, or 50 mg tenecteplase, and 56 patients received 100 mg rt‐PA as the accelerated 90‐minute infusion regimen in this randomized, open‐label study. Tenecteplase and r‐tPA plasma concentrations were measured for 6 hours. Tenecteplase exhibited biphasic elimination from the plasma with a mean initial half‐life of 22 minutes and a mean terminal half‐life of 115 minutes. The mean plasma clearance was 105 mL/min and did not depend on tenecteplase dose over the dose range studied. In comparison, rt‐PA has a fourfold faster plasma clearance. Pharmacokinetic‐pharmacodynamic evaluation showed that a dose of approximately 0.5 mg/kg results in a plasma AUC value that provides a TIMI 3 flow at 90 minutes that is comparable to that reported with accelerated r‐tPA. In conclusion, tenecteplase has a fourfold slower plasma clearance compared with rt‐PA, allowing dosing as an W bolus injection. Weight‐adjusted dosing of tenecteplase may optimize the therapeutic regimen of tenecteplase.
Journal of Controlled Release | 1994
Nishit B. Modi
Abstract Recombinant derived proteins and peptides are becoming increasingly important as therapeutic agents. The successful development of recombinant proteins depends on the proper characterization of their pharmacokinetics and an understanding of the relationship between drug exposure or dose and the pharmacological response. Although many traditional pharmacokinetic principles can be applied to recombinant proteins and peptides, biotechnologically derived agents also pose some new challenges. Pharmacokinetic characterization of proteins is often complicated due to the absence of a specific assay, difficulties in identifying metabolites, endogenous circulating concentrations, and the presence of binding proteins. The ubiquitous distribution of proteases leads to significant degradation and relatively short circulation times in the body. The protein concentration in the circulation may not correlate with the pharmacological effect and it may be difficult to identify or sample the biophase. Numerous methods have been explored for increasing the residence time of proteins and enhancing the pharmacological effect. Some of the techniques that have been employed include site-specific mutagenesis, polymer-modifications and fusion with immunoglobulins, targeting through the use of liposomes or conjugation to toxins, radionuclides and other proteins. An increase in the residence time does not always lead to an enhanced therapeutic effect and these methods have resulted in variable degrees of success. The intricate relationship between pharmacokinetic and pharmacodynamic properties of recombinant proteins is discussed. Examples are presented to illustrate the diversity of approaches that have been employed to improve the therapeutic efficacy of recombinant proteins.
Journal of Cardiovascular Pharmacology | 1995
Nishit B. Modi; Sharon A. Baughman; Brian D. Paasch; Abbie Celniker; Susan Y. Smith
Because activation of the glycoprotein IIbIIIa (GPIIbIIIa) on platelets represents the final common pathway of platelet aggregation, inhibition of fibrinogen binding to the GPIIbIIIa complex provides an excellent target for inhibiting platelet aggregation. Peptides containing the arginine-glycine-aspartic acid (RGD) sequence have been shown to inhibit the binding of fibrinogen to the GPIIbIIIa receptor on platelets competitively. We studied the pharmacokinetics of TP-9201, a synthetic cyclic peptide containing the RGD sequence, in rats and dogs after a 24-h intravenous (I.V.) infusion at three doses. The mean plasma clearance of TP-9201 after intravenous infusions of 30, 150, and 600 mg/kg/day in rats was 20.2, 18.7, and 18.5 ml/min/kg, respectively. In beagles, TP-9201 clearance was 9.0, 7.5, and 7.3 ml/min/kg, corresponding to infusions of 10, 75, and 600 mg/kg/day, respectively. The volume of distribution was larger than plasma volume, and the terminal half-life (t1/2) was short in both species studied ranging from 0.5 to 0.7 h in rats and from 2.5 to 2.6 h in dogs. The results suggest that TP-9201 follows linear pharmacokinetics over the dose range studied. Despite the multiple blood sampling procedure used in the study, there were no hemorrhagic complications. Pharmacodynamic assessment in beagles showed that TP-9201 produces a dose-dependent inhibition of ADP-mediated platelet aggregation. The estimated in vivo IC50 value and sigmoidicity were 124 and 3.5 ng/ml, respectively, suggesting that TP-9201 is a potent GPIIbIIIa antagonist with a steep concentration-effect relationship. TP-9201 is rapidly cleared from the circulation on termination of the intravenous infusion. There is a corresponding reversal of platelet inhibition as TP-9201 is cleared from the circulation.
The Journal of Clinical Pharmacology | 2013
Zhongping Mao; Ann Hsu; Suneel K. Gupta; Nishit B. Modi
A pharmacodynamic model is presented to describe the motor effects (tapping rate, Unified Parkinsons Disease Rating Scale [UPDRS] Part III, and investigator‐rating of ON/OFF, including dyskinesia) of levodopa (LD) in patients with advanced idiopathic Parkinsons disease (PD) treated with immediate‐release (IR) carbidopa–levodopa (CD–LD) or an extended‐release (ER) formulation of CD–LD (IPX066). Twenty‐seven patients participated in this open‐label, randomized, single‐ and multiple‐dose, crossover study. The pharmacodynamic models included a biophase effect site with a sigmoid Emax transduction for tapping and UPDRS and an ordered categorical model for dyskinesia. The pharmacodynamics of LD was characterized by a conduction function with a half‐life of 0.59 hours for tapping rate, and 0.4 hours for UPDRS Part III and dyskinesia. The LD concentration for half‐maximal effect was 1530 ng/mL, 810 ng/mL, and 600 ng/mL for tapping rate, UPDRS Part III, and dyskinesia, respectively. The sigmoidicity of the transduction was 1.53, 2.5, and 2.1 for tapping rate, UPDRS Part III, and dyskinesia, respectively. External validation of the pharmacodynamic model using tapping rate indicated good performance of the model.
Clinical Neuropharmacology | 2016
Hsuan‐Ming Yao; Ann Hsu; Suneel K. Gupta; Nishit B. Modi
ObjectivesIPX066 is an oral, extended-release capsule formulation of carbidopa-levodopa (CD-LD) available in 4 strengths. The goals of this investigation were to assess the dose proportionality of IPX066 and to study the effects of a high-fat, high-calorie meal and of sprinkling the capsule contents on applesauce on the pharmacokinetics of IPX066 in healthy volunteers. MethodsThree open-label studies were conducted. In the first study, subjects received 1 capsule of each IPX066 strength (23.75–95, 36.25–145, 48.75–195, and 61.25–245 mg of CD-LD). In the second study, subjects received 1 and 2 capsules of IPX066 245-mg LD under fasting conditions. In the third study, subjects received 2 capsules of IPX066 245-mg LD under 3 conditions: fasting; following a high-fat, high-calorie breakfast; and with the capsule contents sprinkled on applesauce under fasting conditions. ResultsPeak plasma concentrations (Cmax) and systemic exposure (AUCt, AUCinf) for LD and CD increased dose-proportionally over the range of the IPX066 capsule strengths. Comparison of 1 and 2 IPX066 245-mg LD capsules showed dose-proportional pharmacokinetics for Cmax and AUCt. Sprinkling the capsule contents on applesauce did not affect the pharmacokinetics. A high-fat, high-calorie meal delayed the initial increase in LD concentration by approximately 1 to 2 hours, reduced Cmax by 21%, and increased AUCinf by 13% compared with the fasted state. ConclusionsIPX066 shows dose-proportional pharmacokinetics. Sprinkling the capsule contents on applesauce does not affect the pharmacokinetics; a high-fat, high-calorie meal delayed absorption by 1 to 2 hours, slightly reduced Cmax, and slightly increased extent of absorption.
The Journal of Clinical Pharmacology | 1999
Nishit B. Modi; William Novotny; James D. Reimann; Christopher P. Cannon; Eugene Braunwauld
Sibrafiban is a double prodrug that is converted to the inactive single prodrug and to the active IIb/IIIa antagonist following oral administration. Pharmacokinetics (PK) and pharmacodynamics (PD) of oral sibrafiban and its metabolites were evaluated in patients postacute coronary syndrome receiving once‐ or twice‐daily sibrafiban for up to 28 days at several dose levels. Mean peak concentrations of sibrafiban were < 5 ng/mL. Peak single prodrug concentrations occurred 1.7 1.0 (mean SD) hours after sibrafiban dosing. Total apparent plasma clearance of the single prodrug was 40 15 L/h, and the elimination half‐life was 2.3 0.8 hours. Mean values of the steady‐state pharmacokinetics for total concentrations of the active drug over all doses were: time to peak plasma concentration, 5.0 1.7 hours; apparent clearance, 13.9 3.9 L/h; and half‐life, 11.0 2.8 hours. Once‐daily dosing resulted in high peak‐trough excursions in active drug concentrations: trough concentrations were 21% 6% of peak. Twice‐daily dosing resulted in an AUC for the active drug on Day 28 that was 168% 36% of that on Day 1, and steady‐state trough concentrations were 54% 10% of peak with sustained inhibition of platelet aggregation. Dose‐adjusted steady‐state active drug concentrations increased with increasing age and with decreasing renal function and body weight.
The Journal of Clinical Pharmacology | 2000
James D. Reimann; Nishit B. Modi; William Novotny
Sibrafiban is a double prodrug that is converted to the inactive single prodrug and to the active GP IIb/IIIa antagonist after oral administration. This clinical investigation evaluated whether coadministration of oral aspirin or intravenous heparin would alter the pharmacokinetics or pharmacodynamics of oral sibrafiban. Twenty‐four adult subjects received two of the following four combinations: sibrafiban alone, sibrafiban with ASA, sibrafiban with heparin, and sibrafiban with ASA and heparin, separated by a 2‐week washout period. Concentration profiles of active drug in citrate and EDTA plasma were unchanged with coadministration of ASA or heparin. No pharmacodynamic interaction was seen with coadministration of heparin. Inhibition of platelet aggregation increased 4% to 55%, and Ivy bleeding time increased 58% to 87% with coadministration of sibrafiban and ASA. The combined pharmacodynamic effect of sibrafiban and ASA may indicate a potentially greater therapeutic effect but an increased risk of bleeding when these drugs are used in combination.
Journal of Chromatography B: Biomedical Sciences and Applications | 1997
Brian D. Paasch; Yvonne S. Lin; Seth Porter; Nishit B. Modi; Timothy J Barder
We describe a method for measuring Ro 48-3656 in EDTA rat plasma by neutral pH, reversed-phase high-performance liquid chromatography using a 1.5-microm nonporous silica, C18 analytical column and UV absorbance detection to support pharmacokinetic studies. We also describe a comparison of the 1.5-microm nonporous silica C18 column versus 3.5-microm porous silica C18 columns. The final method using the 1.5-microm nonporous silica column demonstrated good precision (of both quantification and retention time), accuracy and recovery, linearity of dilution and limit of quantification (40 ng/ml Ro 48-3656 using a 20 microl injection). Samples of neat EDTA rat plasma were prepared by ultrafiltration followed by direct injection onto the HPLC column.