Steady-state Trough Levels Research Articles

Plasma concentrations of vigabatrin in epileptic patients.

To measure plasma concentrations of vigabatrin in a group of 30 adult epileptic patients with complex partial seizures (CPS) refractory to conventional antiepileptic drugs. With a view to better defining the drug's dose-response relationships in the presence of concomitant alternative antiepileptic drugs. High-performance liquid chromatographic analysis of blood samples drawn at steady-state trough levels from patients receiving vigabatrin. The steady-state plasma concentrations of vigabatrin showed marked interpatient variability (CV = 59.5%). The mean concentration was 42 +/- 25 micrograms/ml (range 11.5-102.7 micrograms/ml). Nineteen patients (63%) had plasma levels between 20 and 60 micrograms/ml. The plasma clearance of vigabatrin ranged from 0.24 to 1.37 ml/min/kg (mean +/- SD = 0.74 +/- 0.40 ml/min/kg), with a median value of 0.64 ml/min/kg. Concomitant treatment with carbamazepine increased the plasma clearance of vigabatrin from 0.59 ml/min/kg (monotherapy), 0.54 ml/min/kg (co-treated with phenobarbital) and 0.41 ml/min/kg (co-treated with valproic acid) to 0.92 ml/min/kg. Vigabatrin plasma levels show wide interpatient variability, and co-administration with carbamazepine increases vigabatrin's clearance. While there is no relationship between plasma level and anti-epileptic effect, abnormally high levels of the drug may increase toxicity.

Phase I/II Evaluation of Nevirapine Alone and in Combination with Zidovudine for Infection with Human Immunodeficiency Virus

In these Phase I/II open-label clinical trials, 62 persons with human immunodeficiency virus type 1 (HIV-1) infection and CD4+ cell counts < 400/mm3 received nevirapine at doses of 12.5, 50, and 200 mg/day, alone or in combination with zidovudine, 200 mg q8h. Nevirapine was well tolerated in the doses tested. Mean steady-state trough levels were 0.23, 1.1, and 1.9 micrograms/ml for the 12.5, 50, and 200 mg/day doses, respectively. Early suppression of p24 antigen levels and increase in CD4+ cell count were reversed following rapid emergence of virus less susceptible to nevirapine. Resistant strains were isolated from all participants by 8 weeks. Nevertheless, reduction of p24 antigen levels to < 50% of baseline values persisted for 12 weeks or more in four of seven persons who received 200 mg nevirapine/day in combination with zidovudine: these individuals had been antigenemic on long-term zidovudine therapy. This study demonstrates a direct relationship between drug resistance and effects on surrogate markers in HIV-1 infection.

Utilization of Salivary Level Monitoring of Mexiletine in the Therapy of Arrhythmic Patients.

In order to investigate the utility of therapeutic monitoring of mexiletine aided by the saliva drug levels, serum (total and unbound fraction) and saliva drug concentrations were measured in six inpatients with ventricular arrhythmia who were given an oral daily dose of 150 or 300 mg (t. i. d.) of mexiletine hydrochloride.Mexiletine levels in saliva were consistently much higher than the levels in serum of the patients. Saliva level to total and unbound serum drug concentration ratio (S/S ratio) varied markedly among patients from 4.5 to 32.0 and from 9.6 to 68.6, respectively, on the first day of medication. The predicted levels of mexiletine in the serum on day 7 and day 14 using the mean S/S ratio obtained on the first day of medication were almost identical to the observed levels in three of these patients, who showed a small ratio of saliva to total serum concentration, less than about 9 (or 21 for the ratio to unbound concentration). There was no correlation between the mexiletine level in saliva and the salivary flow rate.Four patients who received the drug at a daily dose of 300mg showed almost favorable trough drug levels in the serum total fraction ranging from 0.164 to 0.583 μg/ml, and ventricular premature contraction (VPC) in these patients was almost completely reduced (94.7-100.0%), except for one non-responder. Two patients who received 150 mg of the drug showed steady-state trough levels in the serum total fraction of less than 0.1μg/ml and the VPC of one of these two patients was hardly controlled. We, therefore, increased the daily dose to 300 mg in this patient, who was well controlled thereafter.From these findings, it is suggested that it may be possible to estimate the serum mexiletine levels from the saliva drug levels by using the initial S/S ratios inpatients with ratios of less than about 9.

Evaluation of Bayesian Forecasting for Individualized Gentamicin Dosage in Infants Weighing 1000 g or Less

We evaluated the use of Bayesian forecasting for gentamicin therapy in outborn infants weighing 1000 g or less irrespective of postnatal age. Dosages were individualized using a computer program, guided by early serum gentamicin assays after a loading dose and a database of population kinetics. Steady-state gentamicin levels achieved were compared with those from a regimen based on guidelines. A total of 26 gentamicin courses were individualized in 19 infants of 22 to 33 weeks' gestation, weighing 500 to 1000 g at 1 to 41 days of age. All steady-state trough levels were between 1 and 2.4 mg/L; peak levels were between 4.4 and 9.3 mg/L. The 95% confidence intervals were in almost identical ranges. The prevalence of toxic and suboptimal trough levels was less when compared with that of 23 gentamicin courses based on guidelines in 17 control infants. We conclude that early individualized gentamicin dosage over a range of postnatal age is a practical alternative and serum level distributions appear superior.

Pharmacokinetics of the contraceptive steroids levonorgestrel and gestodene after single and multiple oral administration to women

Little is known about the pharmacokinetics of the two progestins levonorgestrel and gestodene during long-term administration compared with single-dose pharmacokinetics. The predictive value of single-dose administration for the pharmacokinetic behavior of a progestin during long-term treatment was investigated for two triphasic oral contraceptives. One contained levonorgestrel and the other gestodene, each in combination with ethinyl estradiol. In eight Japanese women who received the levonorgestrel-containing formulation over a treatment cycle, steady-state trough levels of levonorgestrel were higher than those obtained by computer simulation based on single-dose administration. An analogous observation was made in a group of 10 white women who received the gestodene-containing formulation. A close correlation between gestodene and sex hormone-binding globulin concentrations was demonstrated for eight subjects; the other two patients already had initially high sex hormone-binding globulin levels. Ethinyl estradiol-induced production of sex hormone-binding globulin seems to be a major factor that contributes to the accumulation of the two progestins in the plasma. Computer simulation, based on single-dose pharmacokinetics, allows an estimation of this contribution.

Alpha-1-antitrypsin augmentation therapy for alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin (A1AT) deficiency is a genetic disorder characterized by low serum levels of A1AT and a high risk for the development of emphysema. A1AT is the principal inhibitor of neutrophil elastase, such that a deficiency of AIAT results in insufficient anti-elastase protection in the lower respiratory tract, thus allowing neutrophil elastase to destroy alveolar structures. The goal of A1AT augmentation therapy in A1AT deficiency is to raise lung A1AT levels and anti-neutrophil elastase capacity to levels that will provide adequate protection against neutrophil elastase, thereby preventing the lung from further elastase-mediated degradation. Studies with intravenous administration of human A1AT (60 mg/kg at weekly intervals) demonstrate that serum A1AT levels increased from an average 33 ± 8 mg/dl pre-infusion to a steady-state trough level of 117 ± 4 mg/dl, well above the projected threshold protective serum level of A1AT. The infused A1AT diffused into the lung and significantly augmented the epithelial lining fluid A1AT levels, rising from an average 0.44 ± 0.16 μM (pre-infusion) to 2.62 ± 1.29 μM at the nadir level just prior to the next infusion. Of critical importance is the fact that the A1AT that diffused into the lung was active as an inhibitor or neutrophil elastase, resulting in significant augmentation of epithelial lining fluid anti-neutrophil elastase capacity and normalization of the lung anti-elastase protection. In the over 800 weekly infusions administered, no significant adverse reactions have occurred. These findings demonstrate that long-term augmentation therapy with weekly infusions of A1AT is a rational, safe, and biochemically effective therapy for A1AT deficiency. Alpha-1-antitrypsin (A1AT) deficiency is a genetic disorder characterized by low serum levels of A1AT and a high risk for the development of emphysema. A1AT is the principal inhibitor of neutrophil elastase, such that a deficiency of AIAT results in insufficient anti-elastase protection in the lower respiratory tract, thus allowing neutrophil elastase to destroy alveolar structures. The goal of A1AT augmentation therapy in A1AT deficiency is to raise lung A1AT levels and anti-neutrophil elastase capacity to levels that will provide adequate protection against neutrophil elastase, thereby preventing the lung from further elastase-mediated degradation. Studies with intravenous administration of human A1AT (60 mg/kg at weekly intervals) demonstrate that serum A1AT levels increased from an average 33 ± 8 mg/dl pre-infusion to a steady-state trough level of 117 ± 4 mg/dl, well above the projected threshold protective serum level of A1AT. The infused A1AT diffused into the lung and significantly augmented the epithelial lining fluid A1AT levels, rising from an average 0.44 ± 0.16 μM (pre-infusion) to 2.62 ± 1.29 μM at the nadir level just prior to the next infusion. Of critical importance is the fact that the A1AT that diffused into the lung was active as an inhibitor or neutrophil elastase, resulting in significant augmentation of epithelial lining fluid anti-neutrophil elastase capacity and normalization of the lung anti-elastase protection. In the over 800 weekly infusions administered, no significant adverse reactions have occurred. These findings demonstrate that long-term augmentation therapy with weekly infusions of A1AT is a rational, safe, and biochemically effective therapy for A1AT deficiency.

Alpha-1-antitrypsin augmentation therapy for alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin (A1AT) deficiency is a genetic disorder characterized by low serum levels of A1AT and a high risk for the development of emphysema. A1AT is the principal inhibitor of neutrophil elastase, such that a deficiency of A1AT results in insufficient anti-elastase protection in the lower respiratory tract, thus allowing neutrophil elastase to destroy alveolar structures. The goal of A1AT augmentation therapy in A1AT deficiency is to raise lung A1AT levels and anti-neutrophil elastase capacity to levels that will provide adequate protection against neutrophil elastase, thereby preventing the lung from further elastase-mediated degradation. Studies with intravenous administration of human A1AT (60 mg/kg at weekly intervals) demonstrate that serum A1AT levels increased from an average 33 ± 8 mg/dl pre-infusion to a steady-state trough level of 117 ± 4 mg/dl, well above the projected threshold protective serum level of A1AT. The infused A1AT diffused into the lung and significantly augmented the epithelial lining fluid A1AT levels, rising from an average 0.44 ± 0.16 μM (pre-infusion) to 2.62 ± 1.29 μM at the nadir level just prior to the next infusion. Of critical importance is the fact that the A1AT that diffused into the lung was active as an inhibitor or neutrophil elastase, resulting in significant augmentation of epithelial lining fluid anti-neutrophil elastase capacity and normalization of the lung anti-elastase protection. In the over 800 weekly infusions administered, no significant adverse reactions have occurred. These findings demonstrate that long-term augmentation therapy with weekly infusions of A1AT is a rational, safe, and biochemically effective therapy for A1AT deficiency.

Human pharmacokinetics and tolerance of oral ganciclovir.

Ganciclovir is a nucleoside analog which inhibits the replication of herpesviruses in vitro and which has been effective by intravenous administration for the treatment of severe cytomegalovirus infection in immunocompromised patients. Because most patients with acquired immunodeficiency syndrome and severe cytomegalovirus infection have required lifelong daily suppressive ganciclovir therapy to control disease progression, oral therapy appears to have practical advantages. We studied the pharmacokinetics of orally administered ganciclovir in four patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. Repeated oral ganciclovir doses (10 to 20 mg/kg every 6 h) were well tolerated. With a 20-mg/kg dose given every 6 h, mean steady-state peak and trough levels were 2.96 and 1.05 microM, respectively, and the area under the concentration-time curve from 0 to 24 h was 47 microM X h. Calculated absorption was 3.0%, based on urinary excretion. Because the levels achieved in serum with oral ganciclovir approximated those required to inhibit cytomegalovirus in vitro, a trial of oral maintenance therapy in immunocompromised patients with severe cytomegalovirus infections seems warranted.

Pharmacokinetics of W-554 (ADD 03055) in epileptic patients.

W-554 (ADD 03055, 2-phenyl-1,3-propanediol dicarbamate) has broad-spectrum antiepileptic activity in animal models of epilepsy. We evaluated its pharmacokinetics and toxicity as an adjunctive medication in eight adult male patients with uncontrolled seizures, treated with phenytoin (n = 4) or carbamazepine (n = 4). After a single 200-mg dose, peak W-554 serum levels of 2.65-4.10 mg/L were achieved in 1-4 h. Half-lives were 11.2-16.1 h and clearance varied from 34.2-64.6 ml/h X kg. The apparent volume of distribution was 0.726-1.046 L/kg. Chronic dosing at 400, 800, 1,200, and 1,600 mg/day resulted in median steady-state trough levels of 5.1, 10.2, 14.6, and 20.3 mg/L. A second kinetic study at the end of chronic dosing indicated no change in volume of distribution, decreased clearance, and increased half-life, compared with single dose data. Urinary excretion of unchanged drug was 13.8-28.6% of the dose. Only one subject had toxicity (mild blurred vision and tremor) possibly attributable to W-554. Seizure control was improved in six of eight subjects, and seizures were less severe in three, while on W-554. Addition of W-554 resulted in increases in serum phenytoin levels, and small decreases in serum carbamazepine levels.

Aminoglycoside pharmacokinetics on a microcomputer.

The authors describe the use of a microcomputer to evaluate an existing dosage regimen and to determine a new regimen and steady-state peak and trough levels for four aminoglycoside antibiotics--amikacin, gentamicin, kanamycin, and tobramycin. The microcomputer program is based on a one-compartment open pharmacokinetic model for the aminoglycosides. It accounts for patients' sex, age, height, obesity, and ascitic compartment. The program is divided into seven subprograms for each of the four aminoglycosides: (1) steady-state peak and trough levels are predicted, based on serum creatinine for a given dosage regimen; (2) a dosage regimen that conforms to 6, 8, 12, 16, or 24 hours is ascertained, based on serum creatinine; (3) a dosage regimen is determined, on the basis of serum creatinine, for desired steady-state peak and trough levels; (4) a dosage regimen that conforms to 6, 8, 12, 16, or 24 hours is ascertained for given aminoglycoside serum levels; (5) a dosage regimen for desired peak and trough levels is ascertained for given aminoglycoside serum levels; (6) a dosage regimen that conforms to 6, 8, 12, 16, or 24 hours is ascertained from data collected using Sawchuk's and Zaske's method; and (7) a dosage regimen, estimated for desired peak and trough levels, is estimated from data collected using Sawchuk's and Zaske's method.

Determining aminoglycoside dosage and blood levels using a programmable calculator

A programmable calculator procedure for the determination of dosage regimens and steady-state peak and trough levels of aminoglycoside antibiotics is described. The calculator is programmed based on a one-compartment open model and first-order elimination of aminoglycosides. A detailed description of the programs and user instructions are presented. The programs allow calculation of intermittent i.v. infusion dosage regimens and steady-state levels, and adjustment of dosage and dosing interval when measured plasma levels differ significantly from predicted levels. The calculator programs provide a rapid means of predicting and modifying dosage regimens and steady-state plasma levels for aminoglycoside antibiotics.