scholarly journals Pharmacokinetics of Phenytoin: Reminders and Discoveries

2009 ◽  
Vol 9 (4) ◽  
pp. 102-104 ◽  
Author(s):  
Donna C. Bergen

Phenytoin Half-Life and Clearance during Maintenance Therapy in Adults and Elderly Patients with Epilepsy. Ahn JE, Cloyd JC, Brundage RC, Marino SE, Conway JM, Ramsay RE, White JR, Musib LC, Rarick JO, Birnbaum AK, Leppik IE. Neurology 2008;71(1):38–43. BACKGROUND: Phenytoin (PHT) is widely used to treat epilepsy in elderly patients, but information on its pharmacokinetics in this population is limited. OBJECTIVE: The purpose of this study was to investigate the effects of age and sex on PHT pharmacokinetics using stable-labeled (SL) isotopes of PHT or fosphenytoin (FOS) administered IV or IM while patients remained on their oral maintenance regimen. METHODS: Subjects were patients 18 years or older with epilepsy, but otherwise healthy, on a maintenance regimen of PHT who were not taking interacting medications. Subjects were given a single injection of a 100 mg dose of SL-PHT or SL-FOS followed by their usual morning PHT dose less 100 mg. Serial blood samples were collected up to 196 hours after the SL dose. Plasma PHT and SL-PHT concentrations were measured by a gas chromatographic-mass spectrometric assay. PHT pharmacokinetics were characterized using a population-based, nonlinear, mixed-effects model. RESULTS: Sixty-three subjects completed the study, 45 of whom were 65 years or older. There was no difference between adult and elderly or men and women in PHT clearance, distribution volume, and elimination half-life. The mean elimination half-life was 40 hours. CONCLUSIONS: Healthy elderly adults appear to have the same phenytoin (PHT) pharmacokinetics as younger adults. Reduced PHT dosage requirements may be due to age-related changes in patients’ sensitivity to the therapeutic and toxic effects of the drug. The prolonged elimination half-life suggests that most patients can take PHT once daily and the time to reach steady-state may extend to 2–3 weeks.

1996 ◽  
Vol 40 (10) ◽  
pp. 2248-2251 ◽  
Author(s):  
T Y Ti ◽  
H S Lee ◽  
Y M Khoo

Steady-state peak and trough concentrations of metronidazole and its metabolites were measured in the sera of 54 surgical patients who were on intravenous metronidazole, 500 mg every 8 h. These patients had no significant renal or hepatic impairment. High-pressure liquid chromatography was used to determine the concentrations of metronidazole and its metabolites. The mean peak and trough metronidazole concentrations were 28.9 +/- 11.0 and 18.0 +/- 9.9 micrograms/ml, respectively. The acid metabolite was not detectable in all the blood specimens. The mean peak concentration of the hydroxy metabolite (MH) was 6.6 +/- 4.3 micrograms/ml, the mean trough concentration of MH was 6.2 +/- 4.2 micrograms/ml, and the MH concentration/metronidazole concentration ratio was 0.4 +/- 0.24. Using a population-based method for the pharmacokinetic analysis and stepwise regression between parameters and covariables (sex, age, and weight), we found that weight showed the highest correlation with the total body clearance (CL). The mean CL was 0.89 +/- 0.3 ml min-1 kg-1 (3.029 liters/h), the mean volume of distribution was 0.73 +/- 0.14 liter/kg, and the mean elimination half-life was 10.6 +/- 4.5 h. For the patients in our study, the CL was lower and the elimination half-life was longer compared with those for healthy volunteers, but the values of these parameters were comparable to those found for hospitalized patients. There was an inverse correlation between age and CL.


2004 ◽  
Vol 48 (3) ◽  
pp. 1061-1064 ◽  
Author(s):  
Agnès Lefort ◽  
Juliette Pavie ◽  
Louis Garry ◽  
Françoise Chau ◽  
Bruno Fantin

ABSTRACT For the treatment of rabbit endocarditis, dalbavancin given once daily (10 mg/kg of body weight for 4 days) or as a single 40-mg/kg dose was active against Staphylococcus aureus with or without reduced susceptibility to glycopeptides, as expected from its good in vitro activity, even in broth supplemented with 90% serum and given its prolonged elimination half-life.


2015 ◽  
Vol 59 (6) ◽  
pp. 3660-3662 ◽  
Author(s):  
J. B. Pain ◽  
M. P. Lê ◽  
M. Caseris ◽  
C. Amiel ◽  
L. Lassel ◽  
...  

ABSTRACTWe describe the pharmacokinetics of dolutegravir (DTG) in a premature neonate after maternal intensification of an antiretroviral (ARV) regimen by adding DTG. During the last 2 weeks of pregnancy, the ARV was tenofovir-emtricitabine, atazanavir-ritonavir, and DTG (50 mg once daily). From the interaction between atazanavir and DTG via CYP3A4 and UGT1A1 and placental efflux transporter inhibition and considering the infant's probable enzymatic immaturity, the DTG elimination half-life was estimated to be 4-fold longer in neonates than in adults.


1983 ◽  
Vol 216 (2) ◽  
pp. 309-315 ◽  
Author(s):  
G J M J Horbach ◽  
S H Yap ◽  
C F A van Bezooijen

Albumin elimination rates were determined in 3-, 12-, 24- and 36-month-old female WAG/Rij rats. No change in elimination half-life was found with age. However, as there was an increase in the whole-body albumin pool, a concomitant increase in albumin clearance was observed at between 12 and 36 months of age. It was concluded that the increase in clearance between 12 and 24 months of age was only due to a change in the animal's physiology, whereas between 24 and 36 months of age it was also due to changes in the albumin molecule. The age-related changes in albumin clearance were thought not to be caused by changes in the albumin excretion via the urine or via the gastrointestinal tract.


2011 ◽  
Vol 55 (9) ◽  
pp. 4218-4223 ◽  
Author(s):  
Marta Boffito ◽  
Akil Jackson ◽  
Alieu Amara ◽  
David Back ◽  
Saye Khoo ◽  
...  

ABSTRACTThe object of this study was to investigate the pharmacokinetics of darunavir-ritonavir and atazanavir-ritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavir-ritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0- to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0- to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC50] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the protein-binding-corrected IC50for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval of 24 h which were above the cutoff used to define therapeutic concentrations.


2009 ◽  
Vol 53 (3) ◽  
pp. 1275-1277 ◽  
Author(s):  
G. A. Pankuch ◽  
P. C. Appelbaum

ABSTRACT The in vitro postantibiotic effects (PAEs), postantibiotic sub-MIC effects (PA-SMEs), and sub-MIC effects of telavancin were determined for 16 gram-positive organisms. Telavancin staphylococcal, streptococcal, and enterococcal PAE ranges were 0.9 to 3.9 h, 0.4 to 6.7 h, and 0.3 to 2.2 h, respectively. The PA-SME ranges (0.4 times the MIC) for staphylococci, streptococci, and enterococci were 6.7 to >10.7 h, >10.7 to >11.0 h, and >10 to >10.8 h, respectively. The extended PAE of telavancin, together with its long elimination half-life in humans, supports once-daily dosing for this investigational drug.


Blood ◽  
2012 ◽  
Vol 119 (14) ◽  
pp. 3276-3284 ◽  
Author(s):  
Carsten Müller ◽  
Niels Murawski ◽  
Martin H. J. Wiesen ◽  
Gerhard Held ◽  
Viola Poeschel ◽  
...  

Abstract Pharmacokinetics of 8 doses of rituximab (375 mg/m2) given in combination with 2-week cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone/prednisolone (CHOP-14) was determined by ELISA in 20 elderly patients with diffuse large B-cell lymphoma (DLBCL) 10 minutes before and after each infusion and 1 week and 1, 2, 3, 6, and 9 months after the last infusion. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling software (NONMEM VI). Concentration-time data were fitted into an open 2-compartment model and total clearance, central compartment volume, intercompartment clearance, and volume of distribution at steady-state (Vdss) were investigated. Total clearance was 9.43 mL/h and Vdss was 9.61 l. Rituximab clearance was reduced (8.21 mL/h vs 12.68 mL/h; P = .003) and elimination half-life was prolonged in women compared with men (t1/2β = 30.7 vs 24.7 days; P = .003). Body weight also affected Vdss (0.1 l increase of Vdss per kilogram above median of 75 kg). A sex-dependent effect and the higher weight of males contribute to their faster rituximab clearance, which might explain why elderly males benefit less from the addition of rituximab to CHOP than females. This trial was registered on www.clinicaltrials.gov as numbers NCT00052936, EU-20243 (RICOVER-60 Trial), EU-20534, and NCT00726700 (Pegfilgrastim Trial).


2001 ◽  
Vol 6 (2) ◽  
pp. 171-176 ◽  
Author(s):  
A. C. S. Lucas ◽  
A. M. Bermejo ◽  
M. J. Tabernero ◽  
P. FernÁNdez ◽  
P. CÁMpora

1984 ◽  
Vol 3 (3) ◽  
pp. 239-243 ◽  
Author(s):  
P.J.A. Leslie ◽  
R.J. Cregeen ◽  
A.T. Proudfoot

1 A woman survived ingestion of 32 g nalidixic acid despite developing lactic acidosis, hyperglycaemia, convulsions and abnormal behaviour. 2 The maximum recorded plasma concentration of nalidixic acid was 185 mg/l and the elimination half-life was 3.2 h. 3 Carboxy-nalidixic acid was demonstrated in the plasma. 4 Previously reported cases of nalidixic acid overdosage are reviewed.


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