Joan Costa

Clinical Pharmacokinetics and Pharmacodynamics of Zolpidem Therapeutic Implications

SummaryZolpidem is an imidazopyridine which differs in structure from the benzodiazepines and zopiclone. It is a strong sedative with only minor anxiolytic, myorelaxant and anticonvulsant properties, and has been shown to be effective in inducing and maintaining sleep in adults. The available evidence suggests that zolpidem produces no rebound or withdrawal effects, and patients have experienced good daytime alertness. Zolpidem 10mg in non-elderly and a reduced dose of 5mg in elderly individuals are clinically effective.In humans, the major metabolic routes include oxidation and hydroxylation; none of the metabolites appears to be pharmacologically active. The pharmacological activity of zolpidem results from selective binding to the central benzo-diazepine receptors of the ωl subtype.Zolpidem is approximately 92% bound to plasma proteins; absolute bioavailability of zolpidem is about 70%. After single 20mg oral doses, typical values of pharmacokinetic variables for zolpidem in humans are: a peak plasma concentration of 192 to 324 µg/L occurring 0.75 to 2.6 hours postdose; a terminal elimination half-life of 1.5 to 3.2 hours; and total clearance of 0.24 to 0.27 ml/min/kg. Zolpidem pharmacokinetics are unchanged during multiple-dose treatment.Zolpidem pharmacokinetics are not significantly influenced by gender. Clearance of zolpidem in children is 3 times higher than in young adults, and is lower in very elderly people. There are no significant differences in the pharmacokinetic parameters between various racial groups. Dosage reduction appears to be prudent in patients with renal disease, and caution should be exercised when prescribing zolpidem to elderly patients with hepatic impairment.Coadministration of haloperidol, cimetidine, ranitidine, chlorpromazine, warfarin, digoxin or flumazenil do not alter the pharmacokinetics of zolpidem; flumazenil predictably antagonises the hypnotic effects of zolpidem. Alertness tends to be reduced when cimetidine is combined with zolpidem. Volunteers treated with imipramine plus zolpidem developed anterograde amnesia.

Double-blind, randomized, placebo-controlled Phase I Clinical Trial of the therapeutical antituberculous vaccine RUTI®

A Phase I interventional Clinical Trial was performed with a potential tuberculosis vaccine, based on detoxified cellular fragments of M. tuberculosis, named RUTI. The objective was to evaluate the safety profile and T-cell immune responses over a 6-month period following subcutaneous inoculation. The double-blind, randomized and placebo-controlled trial was conducted in healthy volunteers, all recruited at one site. RUTI, at each of the four tested doses, starting from 5microg and going up to 200microg, and placebo were inoculated to groups of 4 and 2 volunteers respectively, consecutively. RUTI appeared to be well tolerated as judged by local and systemic clinical evaluation, though vaccine dose dependent local adverse reactions were recorded. T-cell responses of blood lymphocytes to PPD and a number of antigen subunits were elevated, when compared with controls subjects. These results support the feasibility of future evaluation, to be targeted at subjects with latent tuberculosis infection (LTBI).

Composition and antifungal activity of the essential oil from the rhizome and roots of Ferula hermonis

The analysis of the essential oil from rhizome and roots of Ferula hermonis Boiss. (Apiaceae) by GC-FID, GC-MS and ¹³C NMR allowed the identification of 79 constituents, more than 90% of the oil, the major one being α-pinene (43.3%), followed by α-bisabolol (11.1%) and the unusual acetylenic compound 3,5-nonadiyne (4.4%). The antifungal activity of the essential oil before and after fractionation was assayed against several yeasts and filamentous fungi. Purification of the active fractions afforded 3,5-nonadiyne, α-bisabolol, jaeschkeanadiol angelate, α-bisabolol oxide B and trans-verbenol, as well as two purified fractions, one of them (JB73) with 73% of jaeschkeanadiol benzoate and the other with 50% of spathulenol. Determination of MIC and MFC values of all these products evidenced strong antifungal activities for JB73 and 3,5-nonadiyne. Particularly, against the dermatophyte Tricophyton mentagrophytes, MIC and MFC values were 0.25 μg/ml for JB73, and 8 μg/ml for 3,5-nonadiyne, the former being more active than amphotericin B and nystatin.

Simultaneous Population Pharmacokinetic Model for Lopinavir and Ritonavir in HIV-Infected Adults

AbstractBackground: Lopinavir is a protease inhibitor indicated for the treatment of HIV infection. It is coformulated with low doses of ritonavir in order to enhance its pharmacokinetic profile. After oral administration, plasma concentrations of lopinavir can vary widely between different HIV-infected patients. Objective: To develop and validate a population pharmacokinetic model for lopinavir and ritonavir administered simultaneously in a population of HIV-infected adults. The model sought was to incorporate patient characteristics influencing variability in the drug concentration and the interaction between the two compounds. Methods: HIV-infected adults on stable therapy with oral lopinavir/ritonavir in routine clinical practice for at least 4 weeks were included. A concentration-time profile was obtained for each patient, and blood samples were collected immediately before and 1, 2, 4, 6, 8, 10 and 12 hours after a morning lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. First, a population pharmacokinetic model was developed for lopinavir and for ritonavir separately. The pharmacokinetic parameters, interindividual variability and residual error were estimated, and the influence of different patient characteristics on the pharmacokinetics of lopinavir and ritonavir was explored. Then, a simultaneous model estimating the pharmacokinetics of both drugs together and incorporating the influence of ritonavir exposure on oral clearance (CL/F) of lopinavir was developed. Population analysis was performed using nonlinear mixed-effects modelling (NONMEM version V software). The bias and precision of the final model were assessed through Monte Carlo simulations and data-splitting techniques. Results: A total of 53 and 25 Caucasian patients were included in two datasets for model building and model validation, respectively. Lopinavir and ritonavir pharmacokinetics were described by one-compartment models with first-order absorption and elimination. The presence of advanced liver fibrosis decreased CL/F of ritonavir by nearly half. The volume of distribution after oral administration (Vd/F) and CL/F of lopinavir were reduced as α1-acid glycoprotein (AAG) concentrations increased. CL/F of lopinavir was inhibited by ritonavir concentrations following a maximum-effect model (maximum inhibition [Imax] = 1, concentration producing 50% of the Imax [IC50] = 0.36 mg/L). The final model appropriately predicted plasma concentrations in the model-validation dataset with no systematic bias and adequate precision. Conclusion: A population model to simultaneously describe the pharmacokinetics of lopinavir and ritonavir was developed and validated in HIV-infected patients. Bayesian estimates of the individual parameters of ritonavir and lopinavir could be useful to predict lopinavir exposure based on the presence of advanced liver fibrosis and the AAG concentration in an individual manner, with the aim of maximizing the chances of treatment success.

Once- or twice-daily dosing of nevirapine in HIV-infected adults: a population pharmacokinetics approach

OBJECTIVES The aim of this study was to develop and validate a population pharmacokinetic model for nevirapine in a population of HIV-infected adults and to evaluate the influence of nevirapine dosing regimen and patient characteristics on nevirapine trough concentration. METHODS HIV-infected adults receiving oral nevirapine for at least 4 weeks were included. A concentration-time profile was obtained for each patient, and nevirapine concentrations in plasma were determined by HPLC. Pharmacokinetic parameters, inter-individual variability and residual error were estimated using non-linear mixed effects modelling. The influence of patient characteristics on the pharmacokinetics of nevirapine was explored, and the predictive performance of the final model was evaluated in an external data set of observations. RESULTS Totals of 40 and 18 Caucasian patients were included in two data sets for model building and model validation, respectively. A mono-compartmental model with first-order absorption and elimination best described the pharmacokinetics of nevirapine. Body weight influenced oral clearance (CL/F) and volume of distribution (V/F). The estimated population pharmacokinetic parameters (inter-individual variability) for an individual weighing 70 kg were CL/F 2.95 L/h (24%), V/F 95.2 L (30%) and k(a) 1.8 h(-1) (96%). The final model predicted nevirapine concentrations in the external model-validation data set with no systematic bias and adequate precision. Bayesian estimates of nevirapine trough concentrations were lower when nevirapine was administered once instead of twice daily, and nearly half of the patients weighing 90 kg had drug concentrations <3.0 mg/L when nevirapine was dosed once daily. CONCLUSIONS A population model to describe the pharmacokinetics of nevirapine was developed and validated in HIV-infected patients. Body weight influenced CL/F and V/F. Based on Bayesian estimates of individual nevirapine concentrations, twice- instead of once-daily administration of nevirapine would be more optimal in patients weighing >70 kg.

Pharmacological Properties of Hirudin and its Derivatives

SummaryHirudin and its derivatives represent the first parenteral anticoagulants introduced since the discovery of heparin in the early 1900s. Hirudin, the naturally occurring anticoagulant of the leech, is a single peptide chain of 65 amino acids with a molecular weight of about 7000. Recombinant technology has developed methods to produce recombinant forms of hirudin (r-hirudin) in sufficient quantities for therapeutic use.Hirudin is a potent thrombin-specific inhibitor that forms equimolar complexes with thrombin. It represents a new anticoagulant agent in a field in which heparin has been the only available drug for many years. In contrast to heparin, hirudin does not require antithrombin III as a cofactor, is not inactivated by antiheparin proteins, has no direct effects on platelets and may also inactivate thrombin bound to clot or the subendothelium.In humans, experience with r-hirudin in preventing or treating venous thromboembolism is very preliminary. However, r-hirudin achieved promising results in patients with unstable angina, or following coronary angioplasty. In patients with acute myocardial infarction, 3 important clinical trials were stopped because of an excess of bleeding complications. At present, the discovery of a r-hirudin regimen that is more efficacious than heparin and at least as safe needs a reappraisal of the drug in further trials.

Lopinavir/ritonavir pharmacokinetics in HIV and hepatitis C virus co-infected patients without liver function impairment : Influence of liver fibrosis

AbstractBackground and objective: To assess the influence of hepatitis C virus (HCV) co-infection and the extent of liver fibrosis on lopinavir/ritonavir pharmacokinetics in HIV-infected patients without liver function impairment. Methods: Cross-sectional, comparative study enrolling HIV-infected adults receiving lopinavir/ritonavir (400mg/100mg twice daily). HIV/HCV co-infected patients were grouped as having advanced fibrosis (HCV+/FIB+, n = 7) or not (HCV+/FIB−, n = 8) based on the FIB-4 index. A full concentration-time profile was obtained for each patient, and blood samples were collected before (0), and 1, 2, 4, 6, 8, 10 and 12 hours after a lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. Maximum and minimum plasma concentrations (Cmax and Cmin), area under the plasma concentration-time curve from 0 to 12 hours (AUC12), apparent oral clearance at steady state (CLss/F), and apparent volume of distribution after oral administration (Vd/F) were calculated for each individual using a non-compartmental approach. Results: Twenty-six HCV− and 22 HCV+ patients were enrolled. Lopinavir and ritonavir pharmacokinetics were comparable between HCV− and HCV+ patients. However, the Vd/F of lopinavir was 125% higher in HCV+/FIB+ patients than in HCV− patients (p = 0.015) and 107% higher than in HCV+/FIB− (p = 0.040) patients. The CLss/F of ritonavir was 40% lower in HCV+/FIB+ patients than in HCV− patients (p = 0.005) and 44% lower than in HCV+/FIB− patients (p = 0.040). Thus, for ritonavir AUC12, Cmax and Cmin in HCV+/FIB+ patients were 63%, 86% and 100% higher, respectively, when compared with those parameters in HCV− patients (p = 0.005, p = 0.012 and p = 0.015, respectively), and 80%, 86% and 100% higher, respectively, when compared with levels in HCV+/FIB−patients (p = 0.040, p = 0.040 and p = 0.029, respectively). Conclusion: Lopinavir exposure is similar in HIV-infected patients with or without HCV co-infection and without liver function impairment. However, ritonavir exposure may be higher in this setting, particularly in individuals with advanced liver fibrosis.

Absolute bioavailability, pharmacokinetics, and urinary excretion of the novel antimigraine agent almotriptan in healthy male volunteers.

Absolute bioavailability, pharmacokinetics, and urinary excretion of almotriptan, a novel 5‐HT1B/1D receptor agonist, were studied in 18 healthy males following single intravenous (i.v.) (3 mg), subcutaneous (s.c.) (6 mg), and oral (25 mg) doses. Volunteers received each dose in a randomized sequence separated by a 7‐day washout. Blood and urine samples for pharmacokinetic evaluations were taken for up to 24 hours after dosing. The disposition kinetics of almotriptan after i.v. and s.c. administration showed biphasic decline described by a two‐compartment model. The fastest disposition phase was well observed, although estimates of the rate constant showed high variability. After s.c. administration of almotriptan, the bioavailability was 100% with a time to maximum plasma concentration (tmax) of 5 to 15 minutes, whereas after oral administration, the bioavailability was about 70% with a tmax of 1.5 to 3.0 hours. No significant differences were observed between administration routes in the elimination half‐life (t1/2), obtaining mean values ranging from 3.4 to 3.6 hours. The volume of distribution, total clearance, and t1/2 indicated that almotriptan was extensively distributed and rapidly cleared from the body irrespective of dose or route of administration. The primary route of elimination was renal clearance (approximately 50%‐60% of total body clearance). About 65% of the i.v. and s.c. dose and 45% of the oral dose were excreted unchanged in urine in 24 hours, with nearly 90% of this in the first 12 hours. Renal clearance was approximately 2‐ to 3‐fold that of the glomerular filtration rate in man, suggesting that almotriptan is eliminated in part by renal tubular secretion.

Multiple drug interactions – induced serotonin syndrome: a case report

Serotonin syndrome is a potentially life‐threatening disorder of excessive serotoninergic activity often due to drug interactions. We report a case of serotonin syndrome induced by pharmacokinetic and pharmacodynamic interactions between three different selective serotonin‐reuptake inhibitors (SSRI) and possibly ciprofloxacin. Extreme caution is necessary in patients treated with serotonin‐reuptake inhibitors who need to be switched to another antidepressant or when they require the addition of concomitant drugs, especially serotoninergic drugs and isoenzimes of cytochrome P450 inhibitors.

Antifungal compounds from the rhizome and roots of Ferula hermonis.

The antifungal activity of hexane, dichloromethane, methanol and aqueous extracts from the rhizome and root of Ferula hermonis was assayed in vitro by the agar disk diffusion method against a panel of human opportunistic and pathogenic fungi. Among them, the hexane and dichloromethane extracts showed the highest activity particularly against the dermatophytes Microsporum gypseum and Tricophyton mentagrophytes as well as the yeast Candida lactis‐condensi. Activity‐guided fractionation of both extracts using an agar overlay bioautographic method led to the isolation of two antifungal compounds which were identified as the daucane aryl esters jaeschkeanadiol p‐hydroxybenzoate (ferutinin) and jaeschkeanadiol benzoate (teferidin). Determination of minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values of both compounds evidenced a stronger antifungal activity for ferutinin than for teferidin. Particularly, T. mentagrophytes was the most sensitive strain with MIC and MFC values ranging from 8 to 256 µg/mL. Copyright