scholarly journals Multiple-Dose Safety and Pharmacokinetics of Oral Garenoxacin in Healthy Subjects

2003 ◽  
Vol 47 (7) ◽  
pp. 2256-2263 ◽  
Author(s):  
D. A. Gajjar ◽  
A. Bello ◽  
Z. Ge ◽  
L. Christopher ◽  
D. M. Grasela
Keyword(s):  
Healthy Subjects ◽  
Multiple Dose ◽  
Geometric Mean ◽  
Dose Range ◽  
Systemic Exposure ◽  
Psychometric Test ◽  
Once Daily ◽  
Concentration Time ◽  
Wide Range ◽  
Oral Doses

ABSTRACT Garenoxacin (T-3811ME, BMS-284756) is a novel des-F(6) quinolone that has been shown to be effective in vitro against a wide range of clinically important pathogens, including gram-positive and gram-negative aerobes and anaerobes. This study was conducted to evaluate the safety and tolerability of multiple oral doses (100 to 1,200 mg/day) of garenoxacin in healthy subjects and to determine its multiple-dose pharmacokinetics. Forty healthy male and female subjects (18 to 45 years of age) were enrolled in this randomized, double-blind, placebo-controlled, sequential, multiple- and ascending-dose study. Each subject received a once-daily oral dose of garenoxacin (100, 200, 400, 800, or 1,200 mg) or a placebo for 14 days. Blood and urine samples were collected for measurements of garenoxacin by validated liquid chromatography with dual mass spectrometry, and plasma garenoxacin concentration-time data were analyzed by noncompartmental methods. The effects of garenoxacin on Helicobacter pylori, psychometric test performance, and electrocardiograms were assessed, as was drug safety. Over the 14 days of dosing, geometric mean peak concentrations of garenoxacin in plasma (C max) at the 100- and 1,200-mg doses were within the ranges of 1.2 to 1.6 and 16.3 to 24 μg/ml, respectively. The corresponding values for the geometric mean area under the concentration-time curve over the dosing interval (AUC τ ) for garenoxacin in plasma at the 100- and 1,200-mg doses were within the ranges of 11.5 to 15.7 and 180 to 307 μg · h/ml, respectively. Increases in systemic exposure to garenoxacin in terms of AUC and C max were approximately dose proportional over the 100- to 400-mg dose range but demonstrated increases that were somewhat greater than the dose increments at the 800- and 1,200-mg doses. Median values for the time to achieve C max were in the range of 1.13 to 2.50 h for all doses. The mean elimination half-life for garenoxacin in plasma appeared to be independent of dose and ranged from 13.3 to 17.8 h (day 14). Approximately 30 to 50% of an administered garenoxacin dose was excreted unchanged in the urine. At doses of 100 to 400 mg, steady-state concentrations of garenoxacin in plasma appeared to be attained by the fourth dose. Multiple oral doses of garenoxacin were well tolerated and did not demonstrate clinically significant effects on QTc or psychometric test results. Garenoxacin administered alone for 14 days at doses of ≥400 mg demonstrated activity against H. pylori. These results suggest that multiple once-daily oral doses of garenoxacin of up to 1,200 mg are safe and well tolerated and that the pharmacokinetics of garenoxacin support once-daily administration.

scholarly journals POS0672 FIRST-IN-HUMAN STUDY OF GS-5718, AN ORAL IRAK-4 INHIBITOR, IN HEALTHY SUBJECTS: PHARMACOKINETICS, SAFETY, TOLERABILITY, AND ASSESSMENT OF EFFECT OF FOOD AND ACID REDUCING AGENTS ON EXPOSURE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 581.1-581
Author(s):  
K. Anderson ◽  
C. H. Hsueh ◽  
O. Gurtovaya ◽  
A. Mathur ◽  
J. Taylor ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Clinical Laboratory ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Dose Range ◽  
Human Study ◽  
Reducing Agents ◽  
Pharmacokinetic Parameters ◽  
Once Daily ◽  
Effect Of Food

Background:GS-5718 is a potent and selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor in clinical development for treatment of inflammatory diseases.Objectives:The aim of this first-in-human study was to evaluate the pharmacokinetics, safety, and tolerability of GS-5718; and the effect of food and acid-reducing agents (ARA) on GS-5718 pharmacokinetics in healthy subjects.Methods:This was a blinded, randomized, placebo-controlled, single and multiple (once daily for 10 days) oral dose study. Healthy male and female subjects were enrolled in ascending dose cohorts and randomized to receive GS-5718 (15, 50 or 150 mg) or placebo. GS-5718 was administered fasted in the single ascending dose cohorts, and under fed conditions (standard meal) in the multiple dose cohorts. The effects of a high-fat meal and omeprazole (a representative ARA) on GS-5718 50 mg dose pharmacokinetics were also evaluated. Serial blood samples were collected and GS-5718 pharmacokinetic parameters were characterized. Safety was assessed by review of adverse events (AEs), clinical laboratory tests, and vital signs.Results:A total of 74 subjects (n = 62 GS-5718; n = 12 placebo) enrolled and completed study drug treatments in this study. GS-5718 was generally well tolerated at all evaluated dose levels; AEs were mild in severity and no dose-limiting toxicities, serious AEs, nor clinically relevant electrocardiogram or vital sign abnormalities were observed in subjects administered GS-5718. GS-5718 exposure was approximately dose proportional across the evaluated multiple ascending dose range. GS-5718 showed low-to-moderate pharmacokinetic variability with median half-life of 25 to 33 hours and 1.6 to 2.4- fold accumulation at steady-state, which was achieved by Day 5-7 of dosing. Food had no clinically meaningful impact on GS-5718 exposure (AUC and Cmax) at the 50 mg dose. Co-administration of omeprazole with GS-5718 reduced GS-5718 exposure (AUC and Cmax) by 23% and 43%, respectively, at the 50 mg dose.Conclusion:GS-5718, administered once daily, was well tolerated following single or multiple dosing up to 150 mg. The pharmacokinetic and safety profile of GS-5718 support the further development in inflammatory diseases with once-daily administrations.Disclosure of Interests:Kacey Anderson Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Chia-Hsiang Hsueh Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Oksana Gurtovaya Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Anubhav Mathur Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, James Taylor Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Adrian Serone Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Ahmed A. Othman Shareholder of: Gilead Sciences, Employee of: Gilead Sciences

Abstract 455: Assessment of Pharmacokinetic Drug-drug Interaction between LCZ696 and Hydrochlorothiazide

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Hsiu-Ling Hsiao ◽  
Michael Greeley ◽  
Parasar Pal ◽  
Thomas Langenickel ◽  
Gangadhar Sunkara ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Upper Bound ◽  
Healthy Subjects ◽  
Geometric Mean ◽  
Systemic Exposure ◽  
Compartmental Analysis ◽  
Angiotensin Receptor ◽  
Open Label ◽  
Neprilysin Inhibitor ◽  
Drug Drug Interaction

Objective: LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) being developed for the treatment of cardiovascular diseases, including hypertension and heart failure. Ingestion of LCZ696 results in systemic exposure to AHU377 (inactive prodrug of LBQ657, a neprilysin inhibitor) and valsartan (angiotensin receptor blocker). Hydrochlorothiazide (HCTZ) is indicated as first line treatment of hypertension. Since LCZ696 and HCTZ may be co-administered for optimal blood pressure control, this study was conducted to evaluate the pharmacokinetic (PK) drug-drug interaction potential between LCZ696 and HCTZ. Methods: An open-label, three-period, single sequence study in 27 healthy subjects was conducted. In Period 1, subjects received oral HCTZ 25 mg qd x 4 days and were discharged for a 4-10 day washout. In Period 2, subjects received LCZ696 400 mg qd x 5 days, and in Period 3, HCTZ 25 mg qd + LCZ696 400 mg qd x 4 days. Serial PK samples were collected and analyzed by a validated LC-MS/MS method. PK parameters (AUCtau,ss,Cmax,ss) of LCZ696 analytes (LBQ657, valsartan) and HCTZ in plasma were determined using non-compartmental analysis, and the results were statisticallyevaluated. Results: The 90% CIs confidence intervals (CIs) for the geometric mean ratio for AUCtau,ss of HCTZ fell within the ( 0.8 - 1.25) range, while those of Cmax,ss (0.74, 0.70-0.78) fell outside the range, indicating Cmax,ss of HCTZ decreased by 26% when co-administered with LCZ696. Those for AUCtau,ss of LBQ657 fell within the range but the upper bound for Cmax,ss (1.19, 1.10-1.28) was outside the range, indicating Cmax of LBQ657 increased by 19%; the upper bound for valsartan exposures(AUCtau,ss: 1.14, 1.00-1.29; Cmax,ss: 1.16, 0.98-1.37) were above the range, indicating AUCtau,ss and Cmax,ss of valsartan increased by 14%and 16%, respectively. Conclusion: When LCZ696 400mg qd and HCTZ 25mg qd were co- administered, AUCtau,ss of HCTZ was unchanged but Cmax,ss decreased by 26%; AUCtau,ss of LBQ657 was unchanged but Cmax,ss increased by 19%; and lastly, AUCtau,ss and Cmax,ss of valsartan increased by 14%and 16%, respectively. LCZ696 400 mg qd was safe and well tolerated in healthy subjects when administered alone and in combination with HCTZ 25 mg qd.

scholarly journals Fosamprenavir plus Ritonavir Increases Plasma Ketoconazole and Ritonavir Exposure, while Amprenavir Exposure Remains Unchanged

2007 ◽  
Vol 51 (8) ◽  
pp. 2982-2984 ◽  
Author(s):  
Mary B. Wire ◽  
Charles H. Ballow ◽  
Julie Borland ◽  
Mark J. Shelton ◽  
Yu Lou ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
Open Label ◽  
Time Curve ◽  
Once Daily ◽  
Open Label Study ◽  
Label Study ◽  
Concentration Time

ABSTRACT Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV. APV exposure was unchanged, and RTV exposure was slightly increased.

Improved Myocardial T2* in Transfusion Dependent Anemias Receiving ICL670 (Deferasirox).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3600-3600 ◽  
Author(s):  
John B. Porter ◽  
Mark A. Tanner ◽  
Dudley J. Pennell ◽  
Perla Eleftheriou
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Geometric Mean ◽  
Randomized Study ◽  
Iron Concentration ◽  
T Test ◽  
Phase Iii ◽  
Once Daily ◽  
Paired Student ◽  
Wide Range

Abstract ICL670 (deferasirox) is an orally active iron chelator, intended as once daily mono-therapy for the treatment of transfusional iron overload, which has undergone extensive multi-centre Phase II and Phase III trials. Data from such studies suggest that 20mg/kg as a single daily dose will achieve iron balance in the majority of transfusionally dependent patients, whereas 30mg/kg/day typically achieves negative iron balance (Cappellini, Abstract 3619, ASH 2004) (Porter, Abstract 3193, ASH 2004). Patients with transfusion dependent anaemia and iron overload who were entered into these multi-centre studies at UCL Hospitals had myocardial T2* CMR performed at the Royal Brompton Hospital, as part of their routine monitoring, in line with previous clinical management at our centre. Study 108, a non-randomized study, included poorly chelated patients with -thalassemia and other iron overload conditions receiving regular blood transfusion: all patients received 10-30mg/kg/day of ICL670. Study 107 consisted exclusively of transfusion dependent -thalassemia patients, randomized to receive either 8–10h sc DFO (30–50mg/kg/day) or ICL670 (10–30mg/kg/day) with doses stratified for baseline liver iron concentration (LIC). We report here changes in cardiac T2*, LIC and serum ferritin, as well as LVEF in all patients on these two studies treated at UCLH for a mean of 13.1± 0.78 months, in whom CMR was obtained. In a total of 23 patients treated with ICL670, mean age 24.6y (range 9–50y), 18 with transfusion dependent -thalassaemia and 6 other iron overload conditions (2 Pyruvate kinase deficiency, 2 sideroblastic anemia, 2 Diamond Blackfan Anemia), myocardial T2* improved significantly from a pre-treatment geometric mean of 18.0ms to 23.1ms (p = 0.013, paired student t test). In the same patients, serum ferritin fell significantly from 3173 ±410 μg/L to 2451 ±242μg/L (p= 0.023, paired student t test) and LIC fell significantly from 18.3 ±2.2 mg/g dry wt to 10.0 ±1.49 (p= 0.0002, paired student t test). There was no significant change in LVEF before or after treatment over the same period. Patients treated in the DFO arm of study 107 (n=8) also showed a small non-significant increase in myocardial T2* from 18.1 ms to 21.1 ms (p= 0.11), These studies suggest that once daily mono-therapy with ICL670 will be effective at improving myocardial T2* and by inference myocardial iron loading in a wide range of patients with transfusional iron overload. Prospective randomised controlled studies in larger patient numbers are now indicated.

Pharmacokinetics and Pharmacodynamics of Imatinib in a Phase I Trial With Chronic Myeloid Leukemia Patients

2004 ◽  
Vol 22 (5) ◽  
pp. 935-942 ◽  
Author(s):  
Bin Peng ◽  
Michael Hayes ◽  
Debra Resta ◽  
Amy Racine-Poon ◽  
Brian J. Druker ◽  
...  
Keyword(s):  
Steady State ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Drug Exposure ◽  
Dose Range ◽  
Once Daily ◽  
Concentration Time ◽  
The Relationship ◽  
Dose Proportional

Purpose To evaluate the basic pharmacokinetic (PK) characteristics of imatinib mesylate and assess the relationship between the PK and pharmacodynamic (PD) properties of the drug. Patients and Methods The PK and PD properties of imatinib were investigated during a phase I trial that included 64 adult patients with Philadelphia chromosome–positive leukemias. Patients received imatinib orally once or twice daily. PK parameters of imatinib, derived from the plasma concentration–time curves, were determined. PD response, defined as the WBC after 1 month of treatment with imatinib, was used to develop an efficacy model. A maximum inhibition–effect model was used to describe the relationship between reduction in WBC and drug exposure parameters. Results Imatinib exposure was dose proportional after oral administration for the dose range of 25 to 1,000 mg. There was a 1.5- to three-fold drug accumulation after repeated once-daily dosing. Mean plasma trough concentration was 0.57 μg/mL (approximately 1 μmol/L) 24 hours after administration of 350 mg of imatinib at steady-state, which exceeds the 50% inhibitory concentration required to inhibit proliferation of Bcr-Abl–positive leukemic cells. Analysis of PK/PD relationships indicates that the initial hematologic response depends on the administered dose for patients with chronic myeloid leukemia. Conclusion Drug exposure (area under the concentration-time curve) is dose proportional for the dose range of 25 to 1,000 mg, and there is a 1.5- to three-fold drug accumulation at steady-state after once-daily dosing. Analysis of the relationship between PD (WBC reduction) and PK parameters at steady-state indicates that a dose of 400 mg or greater is required for maximal PD effect.

scholarly journals Pharmacokinetic Interaction Study of Ritonavir-Boosted Saquinavir in Combination with Rifabutin in Healthy Subjects

2010 ◽  
Vol 55 (2) ◽  
pp. 680-687 ◽  
Author(s):  
Xiaoping Zhang ◽  
Scott Fettner ◽  
Elke Zwanziger ◽  
Lucy Rowell ◽  
Miklos Salgo
Keyword(s):  
Healthy Subjects ◽  
Pharmacokinetic Interaction ◽  
Interaction Study ◽  
Time Curve ◽  
Once Daily ◽  
Active Moiety ◽  
Concentration Time ◽  
Multiple Doses ◽  
Group 3 ◽  
Group 1

ABSTRACTThe effect of multiple doses of rifabutin (150 mg) on the pharmacokinetics of saquinavir-ritonavir (1,000 mg of saquinavir and 100 mg of ritonavir [1,000/100 mg]) twice daily (BID) was assessed in 25 healthy subjects. Rifabutin reduced the area under the plasma drug concentration-time curve from 0 to 12 h postdose (AUC0-12), maximum observed concentration of drug in plasma (Cmax), and minimum observed concentration of drug in plasma at the end of the dosing interval (Cmin) for saquinavir by 13%, 15%, and 9%, respectively, for subjects receiving rifabutin (150 mg) every 3 days with saquinavir-ritonavir BID. No effects of rifabutin on ritonavir AUC0-12,Cmax, andCminwere observed. No adjustment of the saquinavir-ritonavir dose (1,000/100 mg) BID is required when the drugs are administered in combination with rifabutin. The effect of multiple doses of saquinavir-ritonavir on rifabutin pharmacokinetics was evaluated in two groups of healthy subjects. In group 1 (n= 14), rifabutin (150 mg) was coadministered every 3 days with saquinavir-ritonavir BID. The AUC0-72andCmaxof the active moiety (rifabutin plus 25-O-desacetyl-rifabutin) increased by 134% and 130%, respectively, compared with administration of rifabutin (150 mg) once daily alone. Rifabutin exposure increased by 53% for AUC0-72and by 86% forCmax. In group 3 (n =13), rifabutin was coadministered every 4 days with saquinavir-ritonavir BID. The AUC0-96andCmaxof the active moiety increased by 60% and 111%, respectively, compared to administration of 150 mg of rifabutin once daily alone. The AUC0-96of rifabutin was not affected, andCmaxincreased by 68%. Monitoring of neutropenia and liver enzyme levels is recommended for patients receiving rifabutin with saquinavir-ritonavir BID.

scholarly journals Pharmacokinetics of Telbivudine in Healthy Subjects and Absence of Drug Interaction with Lamivudine or Adefovir Dipivoxil

2006 ◽  
Vol 50 (7) ◽  
pp. 2309-2315 ◽  
Author(s):  
Xiao-Jian Zhou ◽  
Barbara A. Fielman ◽  
Deborah M. Lloyd ◽  
George C. Chao ◽  
Nathaniel A. Brown
Keyword(s):  
Single Dose ◽  
Steady State ◽  
Plasma Concentration ◽  
Healthy Subjects ◽  
Adefovir Dipivoxil ◽  
Geometric Mean ◽  
Time Curve ◽  
Concentration Time ◽  
Plasma Pharmacokinetics ◽  
Plasma Concentration Time Curve

ABSTRACT Two phase I studies were conducted to assess the plasma pharmacokinetics of telbivudine and potential drug-drug interactions between telbivudine (200 or 600 mg/day) and lamivudine (100 mg/day) or adefovir dipivoxil (10 mg/day) in healthy subjects. Study drugs were administered orally. The pharmacokinetics of telbivudine were characterized by rapid absorption with biphasic disposition. The maximum concentrations in plasma (C max) were reached at median times ranging from 2.5 to 3.0 h after dosing. Mean single-dose C max and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) were 1.1 and 2.9 μg/ml and 7.4 and 21.8 μg · h/ml for the 200- and 600-mg telbivudine doses, respectively. Steady state was reached after daily dosing for 5 to 7 days. The mean steady-state C max and area under the plasma concentration-time curve over the dosing interval (AUCτ) were 1.2 and 3.4 μg/ml and 8.9 and 27.5 μg · h/ml for the 200- and 600-mg telbivudine repeat doses, respectively. The steady-state AUCτ of telbivudine was 23 to 57% higher than the single-dose values. Concomitant lamivudine or adefovir dipivoxil did not appear to significantly alter the steady-state plasma pharmacokinetics of telbivudine; the geometric mean ratios and associated 90% confidence interval (CI) for the AUCτ of telbivudine alone versus in combination were 106.3% (92.0 to 122.8%) and 98.6% (86.4 to 112.5%) when coadministered with lamivudine and adefovir dipivoxil, respectively. Similarly, the steady-state plasma pharmacokinetics of lamivudine or adefovir were not markedly affected by the coadministration of telbivudine; the geometric mean ratios and associated 90% CI, alone versus in combination with telbivudine, were 99.0% (87.1 to 112.4%) and 92.2% (84.0 to 101.1%), respectively, for the lamivudine and adefovir AUCτ values. Moreover, the combination regimens studied were well tolerated in all subjects. The results from these studies provide pharmacologic support for combination therapy or therapy switching involving telbivudine, lamivudine, and adefovir dipivoxil for the treatment of chronic hepatitis B virus infection.

scholarly journals Co-Administration of Vonoprazan, Not Tegoprazan, Affects the Pharmacokinetics of Atorvastatin in Healthy Male Subjects

2021 ◽  
Vol 12 ◽  
Author(s):  
Sejung Hwang ◽  
Jae-Wook Ko ◽  
Heechan Lee ◽  
Seokuee Kim ◽  
Bongtae Kim ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Clinical Laboratory ◽  
Systemic Exposure ◽  
Cytochrome P450 3A4 ◽  
Healthy Male ◽  
Open Label ◽  
Once Daily ◽  
New Class ◽  
Inhibitory Activities ◽  
Male Subjects

Potassium-competitive acid blocker is a new class of drugs inhibiting gastric acid. It is controversial that vonoprazan showed the inhibitory activities of cytochrome P450 3A4. This study aimed to evaluate the pharmacokinetics (PK) of atorvastatin and safety when atorvastatin was administered alone and co-administered with vonoprazan or tegoprazan. An open-label, multiple-dose, 3-intervention, 4-sequence, 4-period, partial replicate crossover study was conducted, and three interventions were; one is orally administered atorvastatin 40 mg alone once daily for 7 days, another is atorvastatin co-administered with vonoprazan 20 mg, and the other is atorvastatin co-administered with tegoprazan 50 mg. PK blood samples were collected up to 24 h after the last dose, and PK parameters for atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were estimated by a non-compartmental method. Safety was evaluated, including adverse events and clinical laboratory tests. A total of 28 subjects completed the study. When atorvastatin was co-administered with vonoprazan, the systemic exposures of atorvastatin and atorvastatin lactone significantly increased, and the metabolic ratio of 2-hydroxyatorvastatin significantly decreased. Hypergastrinemia only occurred when atorvastatin was co-administered with vonoprazan. However, the plasma concentration profiles of atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were similar when atorvastatin was administered alone or co-administered with tegoprazan. In conclusion, after multiple doses of atorvastatin co-administered with vonoprazan in healthy subjects, the systemic exposure of atorvastatin and the incidence of hypergastrinemia increased. With tegoprazan, however, those interactions were not observed.

An Open, Phase I Study of Cediranib in Patients with Acute Myeloid Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 895-895
Author(s):  
Walter Fiedler ◽  
Rolf Mesters ◽  
Michael Heuser ◽  
Gerhard Ehninger ◽  
Oliver G. Ottman ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Steady State ◽  
Dose Escalation ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Biologically Active ◽  
Minor Response ◽  
Once Daily ◽  
Oral Doses ◽  
Refractory Aml

Abstract Prognosis is poor for the majority of AML patients, particularly the elderly and those with relapsed or refractory AML, and more effective treatment options are needed. Vascular endothelial growth factor-A (VEGF) and its receptors (VEGFRs) may contribute to the pathophysiology of AML and are considered as potential therapeutic targets. Cediranib (RECENTIN™; AZD2171) is an oral, highly potent and selective VEGF signaling inhibitor with activity versus VEGFR-1, -2 and -3, and additional activity against c-Kit. This two-part study evaluated the safety and tolerability of multiple once-daily oral doses of cediranib in patients with relapsed or refractory AML and elderly patients with de novo or secondary AML, with secondary assessments of pharmacokinetics (PK), pharmacodynamics (PD) and efficacy. Part A was a dose-escalation phase to determine the maximum tolerated dose (MTD); Part B was an expansion phase to explore the MTD and a lower, biologically active dose. A total of 35 patients (mean age, 68 years [range 50–81]; 15 male, 20 female) entered the study and received treatment with cediranib (Part A, n=23; Part B, n=12). Part A comprised 10mg (n=4), 20mg (n=6) and 30mg (n=13) dose cohorts, and intra-patient dose escalation was permitted. In Part B, patients received cediranib 20mg (n=3) or 30mg (n=9). Cediranib ≤30mg was generally well tolerated; diarrhea (n=19), hypertension (n=14) and fatigue (n=13) were the most common adverse events (AEs). Cediranib 30mg was the highest dose studied, and was declared the MTD based on dose-limiting toxicities of hypertension and diarrhea experienced by 3 patients receiving 30mg in Part A. Maximal plasma concentrations at steady-state were attained 0.83–4.1 h post-dosing. Steady-state plasma concentrations were attained after approximately 7 days of repeated once-daily dosing. Following multiple oral doses of cediranib 30mg in Parts A and B, the unbound geometric mean Css,min was 5x the IC50 value required to inhibit proliferation of human umbilical vein endothelial cells in preclinical assays, supporting the once-daily oral dosing regimen. The relationship between PK and two PD parameters (VEGF levels and blood pressure) were investigated and there appeared to be a positive correlation between exposure (Css,max and AUCss) and plasma VEGF levels, but not blood pressure. Time-dependent changes in soluble VEGFR-2 levels were observed. A best investigator assessment of AML objective response according to predefined criteria (Cheson et al, J Clin Oncol2003;21:4642–9) was observed for 6 patients (1 morphological complete remission with incomplete blood recovery [Cri], 4 partial responses and 1 minor response). However, none of the responses resulted in improvement in normal hemopoiesis. No responses were observed in 6 patients with Flt-3 ITD mutations. One patient remained on treatment for 455 days. Once-daily oral cediranib ≤30mg was generally well tolerated in patients with AML, with encouraging preliminary evidence of activity as a monotherapy. The AE and PK profiles of cediranib in AML are consistent with those seen in solid tumors.

Clinical pharmacologic considerations for the phase II/III dose/regimen of the investigational Aurora A kinase (AAK) inhibitor MLN8237 (alisertib): Pharmacokinetics (PK), pharmacodynamics (PD), and exposure-safety relationships.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2597-2597
Author(s):  
Karthik Venkatakrishnan ◽  
Xiaofei Zhou ◽  
Jeffrey Ecsedy ◽  
Hadi Danaee ◽  
Hugh Xiao ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Body Size ◽  
Tumor Cells ◽  
Dose Regimen ◽  
Phase 1 ◽  
Geometric Mean ◽  
Dose Range ◽  
Systemic Exposure ◽  
Phase 2 ◽  
Pharmacologically Active

2597 Background: MLN8237, an oral selective AAK inhibitor, is primarily metabolized by multiple glucuronidation enzymes including the polymorphic UGT1A1. Phase 1 studies included comprehensive PK and PD sampling. We report integrated PK, PD, and PK-safety analyses in support of dose/regimen selection for phase 2/3 studies. Methods: Phase 1 studies in adults with advanced cancers evaluated dosing on d 1-7 in 21-d cycles or d 1-21 in 35-d cycles. Data from 294 patients in 4 phase 1 and 2 phase 2 studies contributed to population PK modeling. PD endpoints included mitotic index (MI) in skin and chromosome alignment and spindle bipolarity (CA/SB) in mitotic tumor cells. Logistic regression analyses evaluated relationships between MLN8237 PK parameters and DLTs (N=86) or CNS adverse events (AEs; n=134) in 2 phase 1 studies. Results: MLN8237 displayed dose-linear PK (5-200 mg/d), described by a 2-compartment model with first order absorption. Covariate analyses did not reveal significant effects of age, body size, sex, UGT1A1 genotype, or creatinine clearance (≥30 mL/min). Exposure-related increases in skin MI and decreases in CA/SB in tumor mitotic cells confirmed AAK inhibition by MLN8237. At the MTD of 50 mg BID (d 1-7 dosing) geometric mean steady-state exposures (48,200 nM.hr) were comparable to those associated with ≥50% CA/SB reductions in mitotic tumor cells (57,300 nM.hr). Exposures at the 21-d MTD (QD dosing) were lower, favoring 50 mg BID (d 1-7 dosing) for further development. At 50 mg BID (d 1-7 dosing) logistic regression relating MLN8237 AUC to DLT rate estimated a DLT probability of 8% (95% CI 3-20%). Similar analyses identified Cmax rather than AUC as the predictor of CNS AEs, supporting BID dosing in adults to reduce peak concentrations while preserving total systemic exposure. Conclusions: MLN8237 exhibits dose-linear PK independent of age, body size, mild or moderate renal impairment, or UGT1A1*28 polymorphism. Exposures achieved at or near 50 mg BID are expected to result in tumor AAK inhibition, supporting a pharmacologically active dose range for future clinical development.

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