Comparison of Pharmacokinetics and Pharmacodynamics of Docetaxel and Cisplatin in Elderly and Non-Elderly Patients: Why Is Toxicity Increased in Elderly Patients?

2004 ◽  
Vol 22 (14) ◽  
pp. 2901-2908 ◽  
Author(s):  
Hironobu Minami ◽  
Yuichi Ohe ◽  
Seiji Niho ◽  
Koichi Goto ◽  
Hironobu Ohmatsu ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Phase Ii ◽  
The Elderly ◽  
Volume Of Distribution ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Two Phase ◽  
Time Curve ◽  
Concentration Time ◽  
Phase Ii Studies ◽  
The Difference

PurposeFollowing phase I studies of docetaxel and cisplatin in patients with non–small-cell lung cancer, the recommended doses of docetaxel were different for elderly (≥ 75 years) and non-elderly (< 75 years) patients. To elucidate the mechanism of the difference, the pharmacokinetics of docetaxel and cisplatin were investigated in two phase II studies separately conducted in elderly and non-elderly patients.Patients and MethodsTwenty-seven elderly and 25 non-elderly patients were treated with three weekly administrations of docetaxel and cisplatin every 4 weeks. Doses of docetaxel were 20 and 35 mg/m2for elderly and non-elderly patients, respectively. All patients received 25 mg/m2of cisplatin. The pharmacokinetics and pharmacodynamics of docetaxel and cisplatin were compared in elderly and non-elderly patients.ResultsThere were no differences in pharmacokinetics of docetaxel or cisplatin between elderly versus non-elderly patients with regard to clearance and volume of distribution. In the pharmacodynamic analysis, neutropenia was positively correlated with the area under the concentration-time curve for docetaxel but not for cisplatin. In evaluating the relationship between neutropenia and the area under the concentration-time curve of docetaxel, elderly patients experienced greater neutropenia than those predicted by a pharmacodynamic model developed in non-elderly patients; the residual for prediction of the percent change in neutrophil count was −11.2% (95% CI, −21.8 to −0.5%).ConclusionThe pharmacokinetics of docetaxel and unchanged cisplatin were not different between elderly and non-elderly patients. The elderly patients were more sensitive to docetaxel exposure than the non-elderly patients, resulting in the different recommended doses for the phase II studies.

Metronidazole Elimination is Preserved in the Elderly

1990 ◽  
Vol 9 (3) ◽  
pp. 155-159 ◽  
Author(s):  
Steffen Loft ◽  
Charlotte Egsmose ◽  
Jesper Sonne ◽  
Henrik Enghusen Poulsen ◽  
Martin Døssing ◽  
...  
Keyword(s):  
Old Age ◽  
Half Life ◽  
Renal Excretion ◽  
The Elderly ◽  
Volume Of Distribution ◽  
Time Curve ◽  
Concentration Time ◽  
Age Related ◽  
Young Subjects ◽  
Hydroxy Metabolite

1 The disposition of metronidazole and its major metabolites was compared in 11 subjects aged 86 ± 6 years and 8 aged 30 ± 6 years. 2 The plasma clearance of metronidazole was 1.20 ± 0.53 and 1.25 ± 0.22 ml min-1 kg -1, the volume of distribution 0.77 ± 0.27 and 0.77 ± 0.09 1 kg -1 and the half-life 7.8 ± 1.9 and 7.2 ± 0.9 h in elderly and young subjects, respectively (P > 0.05). 3 The area under the plasma concentration-time curve of the hydroxy metabolite was 32 ± 14 and 21 ± 3 mM min-1 (P < 0.05) whereas its half-life was 21 ± 14 and 12 ± 2 h (P < 0.05) in the elderly and young subjects, respectively. 4 The recovery in the urine of metronidazole and its metabolites was 42 ± 21% and 87 ± 6% of dose in elderly and young subjects, respectively (P < 0.05). With this reservation the only elimination pathways of metronidazole affected by old age were the renal excretion of unchanged compound and the hydroxy metabolite. 5 It is concluded that the ability to eliminate metronidazole is preserved in old age and that age-related dose adjustments are not necessary.

Mitomycin C, Carboplatin and Protracted Venous Infusion 5-Fluorouracil in Advanced Oesophago–gastric and Pancreatic Cancer: Results of Two Phase II Studies

2003 ◽  
Vol 15 (3) ◽  
pp. 92-97
Author(s):  
M Kelleher ◽  
N.C Tebbutt ◽  
D Cunningham ◽  
J Andreyev ◽  
M Allen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mitomycin C ◽  
Phase Ii ◽  
Two Phase ◽  
Phase Ii Studies ◽  
Venous Infusion

scholarly journals Pharmacokinetic Interactions of Maraviroc with Darunavir-Ritonavir, Etravirine, and Etravirine-Darunavir-Ritonavir in Healthy Volunteers: Results of Two Drug Interaction Trials

2011 ◽  
Vol 55 (5) ◽  
pp. 2290-2296 ◽  
Author(s):  
Thomas N. Kakuda ◽  
Samantha Abel ◽  
John Davis ◽  
Julia Hamlin ◽  
Monika Schöller-Gyüre ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Volunteers ◽  
Potent Inhibitor ◽  
Cytochrome P450 3A ◽  
Short Term ◽  
Two Phase ◽  
Time Curve ◽  
Safety Issues ◽  
Concentration Time ◽  
Crossover Studies

ABSTRACTThe effects of darunavir-ritonavir at 600 and 100 mg twice daily (b.i.d.) alone, 200 mg of etravirine b.i.d. alone, or 600 and 100 mg of darunavir-ritonavir b.i.d. with 200 mg etravirine b.i.d. at steady state on the steady-state pharmacokinetics of maraviroc, and vice versa, in healthy volunteers were investigated in two phase I, randomized, two-period crossover studies. Safety and tolerability were also assessed. Coadministration of 150 mg maraviroc b.i.d. with darunavir-ritonavir increased the area under the plasma concentration-time curve from 0 to 12 h (AUC12) for maraviroc 4.05-fold relative to 150 mg of maraviroc b.i.d. alone. Coadministration of 300 mg maraviroc b.i.d. with etravirine decreased the maraviroc AUC12by 53% relative to 300 mg maraviroc b.i.d. alone. Coadministration of 150 mg maraviroc b.i.d. with etravirine-darunavir-ritonavir increased the maraviroc AUC123.10-fold relative to 150 mg maraviroc b.i.d. alone. Maraviroc did not significantly affect the pharmacokinetics of etravirine, darunavir, or ritonavir. Short-term coadministration of maraviroc with darunavir-ritonavir, etravirine, or both was generally well tolerated, with no safety issues reported in either trial. Maraviroc can be coadministered with darunavir-ritonavir, etravirine, or etravirine-darunavir-ritonavir. Maraviroc should be dosed at 600 mg b.i.d. with etravirine in the absence of a potent inhibitor of cytochrome P450 3A (CYP3A) (i.e., a boosted protease inhibitor) or at 150 mg b.i.d. when coadministered with darunavir-ritonavir with or without etravirine.

scholarly journals Safety, toleration, and pharmacokinetics of intravenous azithromycin.

1996 ◽  
Vol 40 (11) ◽  
pp. 2577-2581 ◽  
Author(s):  
D R Luke ◽  
G Foulds ◽  
S F Cohen ◽  
B Levy
Keyword(s):  
Half Life ◽  
Active Drug ◽  
Slow Release ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Concentration Time ◽  
Elimination Half ◽  
The Mean ◽  
Male Subjects

To date, the clinical pharmacology of large intravenous doses of azithromycin has not been described. In the present study, single 2-h intravenous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and two received placebo) of healthy male subjects. Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [good] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous infusion. Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cramping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithromycin was well tolerated. Because of the standardized 1-mg/ml infusates, all subjects in the 4-g dosing group complained of an urgent need to urinate. There were no consistent trends in endogenous motilin levels throughout the study. The maximum concentration of azithromycin in serum (10 micrograms/ml after a 4-g dose) and the area under the concentration-time curve (82 micrograms.h/ml after a 4-g dose) were dose related. The mean pharmacokinetic parameters were an elimination half-life of 69 h, total systemic clearance of 10 ml/min/kg, and a volume of distribution at steady state of 33.3 liters/kg. The pharmacokinetic results suggest that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug. Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable concentrations may persist in serum for 10 days or more.

Combination of Oxaliplatin Plus Irinotecan in Patients With Gastrointestinal Tumors: Results of Two Independent Phase I Studies With Pharmacokinetics

1999 ◽  
Vol 17 (6) ◽  
pp. 1751-1751 ◽  
Author(s):  
Ernesto Wasserman ◽  
Caroline Cuvier ◽  
François Lokiec ◽  
François Goldwasser ◽  
Salima Kalla ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Two Phase ◽  
Phase I Studies ◽  
Phase Ii Studies ◽  
Minute Period ◽  
Grade 3 ◽  
Febrile Episodes

PURPOSE: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. PATIENTS AND METHODS: Patients with a performance status (PS) of ≤2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m2 for oxaliplatin and 150 to 250 mg/m2 for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m2 plus irinotecan 200 mg/m2 in one study and oxaliplatin 110 mg/m2 plus irinotecan 250 mg/m2 in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2. At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION: This combination is feasible, with activity in 5-FU–resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.

Phase II Study of Area Under the Plasma-Concentration-Versus-Time Curve–Based Carboplatin Plus Standard-Dose Intravenous Etoposide in Elderly Patients With Small-Cell Lung Cancer

1999 ◽  
Vol 17 (11) ◽  
pp. 3540-3545 ◽  
Author(s):  
Hiroaki Okamoto ◽  
Koshiro Watanabe ◽  
Yutaka Nishiwaki ◽  
Kiyoshi Mori ◽  
Yuzoh Kurita ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Plasma Concentration ◽  
Elderly Patients ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Standard Dose ◽  
Small Cell ◽  
Small Cell Lung ◽  
Time Curve

PURPOSE: The target area under the plasma-concentration-versus-time curve (AUC)–based dosing of carboplatin using Calvert's formula is expected to result in more acceptable toxicity and greater efficacy in elderly patients with small-cell lung cancer (SCLC) than the body surface area–based dosing strategy. This phase II study was designed to determine the toxicity and efficacy of carboplatin based on Calvert's formula plus the standard dose of intravenous etoposide for elderly patients with SCLC. PATIENTS AND METHODS: Carboplatin, dosed to a target AUC of 5 × (24-hour creatinine clearance + 25), was given intravenously on day 1 and etoposide 100 mg/m2 was given intravenously on days 1, 2, and 3. Patients aged ≥ 70 years old with a performance status of 0 to 2 were eligible. RESULTS: Thirty-six patients were enrolled onto the study. The patient characteristics were as follows: median age, 73 years; limited disease (LD), 16 patients; and extensive disease (ED), 20 patients. Grades 3 and 4 leukopenia occurred in 57% and 3% of patients, and grades 3 and 4 thrombocytopenia occurred in 40% and 11% of patients, respectively. There was one treatment-related death due to hemoptysis. Other toxicities were relatively mild. There were two complete responses and 25 partial responses, for a response rate of 75%. The median survival time was 10.8 months (LD, 11.6 months; ED, 10.1 months), and the 1-year survival rate was 47%. CONCLUSION: This carboplatin/etoposide combination chemotherapy is an active and relatively nontoxic regimen in elderly patients with SCLC, which suggests that the combination may be suitable for randomized controlled trials.

scholarly journals MA07.01 Updated Pooled Analysis of CNS Endpoints in Two Phase II Studies of Alectinib in ALK+ NSCLC

2017 ◽  
Vol 12 (1) ◽  
pp. S377
Author(s):  
Sai-Hong Ignatius Ou ◽  
Leena Gandhi ◽  
Alice Shaw ◽  
Ramaswamy Govindan ◽  
Mark Socinski ◽  
...  
Keyword(s):  
Phase Ii ◽  
Pooled Analysis ◽  
Two Phase ◽  
Phase Ii Studies
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