A. Dominguez-Gil Hurle

Oral absorption of ofloxacin administered together with aluminum.

A clinical study was carried out to establish the influence of aluminum on the oral absorption of ofloxacin. Ten healthy volunteers were included in a crossover study based on a Latin square design. The treatments that all volunteers received were A, consisting of 400 mg of ofloxacin, and B, consisting of 400 mg of ofloxacin plus 11 g of colloidal aluminum phosphate. The absorption constant and other ofloxacin parameters were calculated from data on levels in plasma by using model-independent calculation methods. There were no statistically significant differences between the mean values of the areas under the curve corresponding to the administration of ofloxacin alone and those of ofloxacin with aluminum. Regarding the other pharmacokinetic parameters, a significant difference between the absorption constants was found. The presence of aluminum reduces the absorption rate of this quinolone but does not modify the percentage of the absorbed dose.A clinical study was carried out to establish the influence of aluminum on the oral absorption of ofloxacin. Ten healthy volunteers were included in a crossover study based on a Latin square design. The treatments that all volunteers received were A, consisting of 400 mg of ofloxacin, and B, consisting of 400 mg of ofloxacin plus 11 g of colloidal aluminum phosphate. The absorption constant and other ofloxacin parameters were calculated from data on levels in plasma by using model-independent calculation methods. There were no statistically significant differences between the mean values of the areas under the curve corresponding to the administration of ofloxacin alone and those of ofloxacin with aluminum. Regarding the other pharmacokinetic parameters, a significant difference between the absorption constants was found. The presence of aluminum reduces the absorption rate of this quinolone but does not modify the percentage of the absorbed dose.

COMPARISON OF METHODS FOR THE PREDICTION OF PHENYTOIN CONCENTRATIONS

A comparison was made of different methods for the prediction of the serum concentrations of phenytoin (PHT) at steady‐state with a view to determining which of them had the best predictive performance. The methods employed calculated the predicted concentrations based on a dose steady‐state concentration pair. Two of the methods used involved solving the Michaelis‐Menten equation, determination of a single parameter in each individual and maintaining the Km (Method A) or Vmax (Method B) values at a constant. Methods C and D were Bayesian techniques that used population parameters determined in a population studied by us (Method C) and parameters drawn from the literature (Method D). Calculation of bias and precision suggests that Method C is the most suitable of those studied, with a mean prediction error (ME) of 0·56 ± 2·16 mg/litre, a mean absolute error (MAE) of 1·76 ± 1·31 mg/litre and a root mean squared prediction error (RMSE) of 2·17 mg/litre. Method C was also the method that showed the lowest percentage of underestimation (5·26%) and overestimation (10·53%).

Effect of sodium valproate on phenobarbital serum levels in children and adults.

Summary: The influence of sodium valproate on serum levels of phenobarbital during combination treatment was studied in 29 children and 50 adults with epilepsy. Steady-state drug levels in serum were determined immediately prior to drug administration using immunoenzymatic analysis. The serum level/dose ratio of phenobarbital increased significantly (p > 0.001) when sodium valproate was added to the treatment. The increase had a mean value of 50.9% in adults and 112.5% in children, suggesting marked interindividual variability in the intensity of the interaction. Almost half of the patients required a decrease in the dose of phenobarbital prescribed. The interaction was more pronounced in patients with high serum levels of phenobarbital, while the dose of phenobarbital and the serum levels and dose of sodium valproate did not seem to affect the extent of the interaction. Close monitoring of the serum levels of phenobarbital is recommended during simultaneous treatment with sodium valproate.

Effect of renal impairment on distribution of ofloxacin.

A study was made of the plasma and distribution kinetics of ofloxacin administered at a dosage of 400 mg orally to a group of healthy volunteers and a group of patients with renal impairment. Blood and blister fluid samples were taken at programmed times from all individuals included in the study. The analytical techniques for the determination of ofloxacin in both fluids were a plate diffusion method and a high-performance liquid chromatographic technique. The fitting of the experimental data to the kinetic model used was done with the help of the AUTOAN 2 and NONLIN 84 computer programs. In the groups of healthy volunteers, the elimination half-life mean values were found to be 5.1 and 5.9 h in plasma and blister fluid, respectively. The maximum concentration reached in plasma (3.9 micrograms/ml) proved to be slightly higher than that in interstitial tissue fluid (2.8 micrograms/ml). In the patients with renal impairment, the maximum concentrations in both plasma and blister fluid were significantly increased, in the order of 5 to 8 micrograms/ml in the former and 3 to 4 micrograms/ml in interstitial tissue fluid. The parameters seen to undergo an increase as a result of the renal impairment were the area under the curve of the plasma-time levels, the area under the curve of the blister fluid-time levels, and the elimination half-life in plasma and blister fluid. The degree of absorption and the access capacity of the drug to interstitial tissue fluid remained constant.A study was made of the plasma and distribution kinetics of ofloxacin administered at a dosage of 400 mg orally to a group of healthy volunteers and a group of patients with renal impairment. Blood and blister fluid samples were taken at programmed times from all individuals included in the study. The analytical techniques for the determination of ofloxacin in both fluids were a plate diffusion method and a high-performance liquid chromatographic technique. The fitting of the experimental data to the kinetic model used was done with the help of the AUTOAN 2 and NONLIN 84 computer programs. In the groups of healthy volunteers, the elimination half-life mean values were found to be 5.1 and 5.9 h in plasma and blister fluid, respectively. The maximum concentration reached in plasma (3.9 micrograms/ml) proved to be slightly higher than that in interstitial tissue fluid (2.8 micrograms/ml). In the patients with renal impairment, the maximum concentrations in both plasma and blister fluid were significantly increased, in the order of 5 to 8 micrograms/ml in the former and 3 to 4 micrograms/ml in interstitial tissue fluid. The parameters seen to undergo an increase as a result of the renal impairment were the area under the curve of the plasma-time levels, the area under the curve of the blister fluid-time levels, and the elimination half-life in plasma and blister fluid. The degree of absorption and the access capacity of the drug to interstitial tissue fluid remained constant.

Influence of length of treatment on the interaction between phenobarbital and phenytoin

A combination of anti‐epileptic drugs gives rise to interactions that modify their disposition kinetics. To discover the clinical relevance of such interactions it is necessary to establish their direction and magnitude. Phenytoin may interact with phenobarbital either as an inducer or an inhibitor of metabolism, depending on the length of treatment with the combination of both drugs. Data obtained in six, adult, epileptic patients treated with phenobarbital alone, and later with a phenobarbital ‐phenytoin combination, showed that the serum levels of the barbiturate undergo an increase during the first year of treatment with the combination therapy. From this point onwards a decrease is observed in the levels of phenobarbital, to return after about 2 years to values similar to those observed with monotherapy.

Prediction of Imipramine Serum Levels in Enuretic Children by a Bayesian Method: Comparison with Two Other Conventional Dosing Methods

The aim of the present study was to characterize the kinetic behavior of imipramine (IMI) and desipramine in enuretic children and to evaluate the performance of different methods for dosage prediction based on individual and/or population data. The study was carried out in 135 enuretic children (93 boys) ranging in age between 5 and 13 years undergoing treatment with IMI in variable single doses (25–75 mg/day) administered at night. Sampling time was one-half the dosage interval at steady state. The number of data available for each patient varied (1–4) and was essentially limited by clinical criteria. Pharmacokinetic calculations were performed using a simple proportional relationship (method 1) and a multiple nonlinear regression program (MULTI 2 BAYES) with two different options: using the ordinary least-squares method (method 2) and the least-squares method based on the Bayesian algorithm (method 3). The results obtained point to a coefficient of variation for the level/dose ratio of the drug (58%) that is significantly lower than that of the metabolite (101.4%). The forecasting capacity of method 1 is deficient both regarding accuracy [mean prediction error (MPE) = −5.48 \Pm 69.15] and precision (root mean squared error = 46.42 \Pm 51.39). The standard deviation of the MPE (69) makes the method unacceptable from the clinical point of view. The more information that is available concerning the serum levels, the greater are the accuracy and precision of methods (2 and 3). With the Bayesian method, less information on drug serum levels is needed to achieve clinically acceptable predictions.

Pharmacogenetic analysis of SNPs in genes involved in the pharmacokinetics and response to lopinavir/ritonavir therapy.

Despite the known benefits and the experienced use of lopinavir/ritonavir (LPV/r) in the management of HIV infection, important interindividual variability in the pharmacokinetics (PKs) and the response to treatment with standard doses of this drug has been observed. Host genetic factors have been recently suggested as being responsible for part of this variability as they may affect the expression and functional activity of many proteins involved in the kinetic behavior, the immune recovery or the adverse effects related to LPV/r. Here, we present a genetic association study in 106 HIV-infected individuals collected over a period of 5 years with the aim of identifying and confirming single nucleotide polymorphisms (SNPs) with a significant influence on the PK parameters of LPV/r, the immunovirological response or toxicity derived from treatment with the studied drug. Genotyping was performed by MALDI-TOF and KASPar; LPV/r plasma concentrations were quantified using high-performance liquid chromatography with an ultraviolet detection system and the PK parameters were estimated using Bayesian algorithms. Genetic association analysis was performed with SPSS. The most significant associations were found between SNPs in the dopamine receptor D3 gene and the PK of LPV/r. Additionally, other suggestive relationships were established between genetic factors and the response during treatment with this drug. Thereby, identifying HIV-infected individuals who are at increased risk of achieve non-optimal LPV/r plasma concentrations with the emergence of toxicity, drug resistance or absence of clinical response could be helpful as a tool to optimize the LPV/r-based antiretroviral therapy.

Influence of the number of daily pills and doses on adherence to antiretroviral treatment: a 7‐year study

Antiretroviral treatment (ART) is hampered by complicated regimens, high pill burden, drug–drug interactions, and frequent short‐ and long‐term adverse effects, leading to decreased adherence. Over recent years, considerable effort has been directed at developing regimens that are less burdening. We undertook a 7‐year retrospective study of the records of 264 HIV‐infected subjects enrolled in a pharmaceutical care programme to document the progress made and to study the influence of the number of ART pills and doses on the level of treatment adherence.

In vitro interaction between HAPA-gentamicin B and penicillins

Abstract The inactivation kinetics of a new aminoglycoside shortly to be introduced in clinical practice, HAPA-gentamicin-B, by 3 commonly used penicillins (ampicillin, carbenicillin and ticarcillin) were studied in vitro considering the influence of the HAPA-B-penicillin concentrations ratio on the kinetics of the process. In all cases the kinetic process was of pseudo-first order. The degree of inactivation of HAPA-B depends on the type of penicillin it is combined with and on the percentage of the penicillin compound in the sample. The percentage of inactivated HAPA-B was maximum with ampicillin and minimum with ticarcillin. Comparison of the results obtained in the present study with those found in the literature concerning other aminoglycosides shows that HAPA-B is less susceptible to inactivation by penicillins than most of the antibiotics of this group.