Drug Concentrations In Patients Research Articles

Two cases of pregabalin neurotoxicity in chronic kidney disease patients.

Sir We report two cases of newly presenting pregabalin neurotoxicity in chronic kidney disease (CKD) patients. A 67-year-old man was referred to our nephrology department for consultation. He had been admitted to the department of orthopedics because of spinal stenosis and had undergone surgery 5 weeks earlier. He had started hemodialysis 3 months previously. Upon presentation, he was in a deep drowsy mental state. He was also suffering from generalized myoclonic jerk, aphasia and dysarthria of several days duration. We did not detect a brain lesion on magnetic resonance imaging or computed tomography. No medications were being given that could have induced his neurologic symptoms and signs. No laboratory abnormalities were detected that would explain his neurologic deficits. However, pregabalin had been started at a dosage of 300 mg/day 2 weeks before presentation, and the dosage had been increased to 450 mg/day 7 days previously. We concluded that his neurologic deficits were the result of pregabalin toxicity. Pregabalin was immediately withdrawn and an additional three hemodialysis sessions were performed, after which the patient became mentally alert and the generalized myoclonus, aphasia and dysarthria completely disappeared. The second case is that of a 43-year-old man who was admitted for evaluation of nausea, vomiting and general weakness. He was diagnosed with diabetes mellitus and CKD Stage 4. Three days after admission, he complained of pain around the posterior neck region and in both shoulders. He was diagnosed with fibromyalgia and commenced therapy with pregabalin. After receiving a 75 mg/day dose of pregabalin for 2 days, he developed a drowsy mental state and myoclonus of both upper extremities was detected. His calculated creatinine clearance (CCr) by Cockcroft–Gault formula was 25.7 mL/min. We suspected pregabalin toxicity and immediately withdrew it. Thereafter, he fully recovered from the drowsiness, disorientation and myoclonus. Pregabalin is well absorbed orally and has a bioavailability of >90%. It is completely excreted into the urine without hepatic metabolism. It is usually suggested that pregabalin doses be decreased by ∼50% for each 50% decline in CCr to achieve similar plasma drug concentrations in patients with impaired renal function [1]. Pregabalin toxicity in CKD patients has very rarely been reported [2–4]. Two cases have occurred in hemodialysis patients, whereas one case occurred in a patient undergoing peritoneal dialysis. Our first patient was also undergoing hemodialysis, whereas the second one was a CKD Stage 4 patient. To the best of our knowledge, there have been no reports of pregabalin toxicity in a Stage 4 CKD patient. In our first patient, although the initial dosage of pregabalin was high, there were no severe symptoms and signs before the increase in dosage. This might have been the result of drug removal by regular hemodialysis. Although we reduced the dosage of pregabalin in accordance with his renal function in the other patient, pregabalin neurotoxicity did occur. We think that a 75 mg/day dosage might not increase the serum level of pregabalin enough to induce neurologic impairment, although we did not measure the drug level in the serum. One should exercise prudence when prescribing this drug in a CKD patient and adjust the dosage in accordance with renal function. The drug should be immediately withdrawn if neurologic symptoms and signs appear.

Population pharmacokinetics of a propofol bolus administered in patients with major burns

Objective In operating theaters and burn units, propofol is commonly used for sedation and anesthesia in patients with major burns. This study determined the population pharmacokinetics of propofol in burns and identified clinically significant covariates. Method Seventeen adults, age 42 ± 10 (mean ± SD) years, with 41 ± 19% total body surface area burns, were enrolled at 16 ± 14 days after-burn. Non-burn adults ( n = 19) served as controls. After an intravenous bolus of 2 mg/kg propofol, the plasma concentration was determined at designated times for up to 4.5 h. Concentration–time profiles were analyzed using nonlinear mixed-effect modeling. Results A three-compartment model gave the best fit. The volume of distribution of the central compartment ( V 1) was considerably greater in the burned than non-burned group (48.4 L vs. 27.6 L, respectively). The clearances of the central ( CL 1) and slow peripheral ( CL 3) compartments were higher in burn patients (4.2 L/min vs. 1.7 L/min and 3.6 L/min vs. 1.1 L/min, respectively). Adding the covariates BURN to V 1, CL 1, and CL 3 and WT (weight) to CL 1 significantly improved the model performance. Conclusion The pharmacokinetic characteristics of a propofol bolus administered in patients with major burns were enhanced clearance and expanded volume of distribution. BURN and WT were the important covariates. For sedation or anesthesia induction, a higher than recommended dose of propofol may be required to maintain therapeutic plasma drug concentrations in patients with severe burns. Vigilance regarding the burned individual and careful titration of hypnotics to the desired effect cannot be overemphasized.

Tolerability and Patient/Physician Satisfaction with Subcutaneously Administered Methotrexate Provided in Two Formulations of Different Drug Concentrations in Patients with Rheumatoid Arthritis~!2010-01-14~!2010-02-08~!2010-03-18~!

Objectives:To determine preference, satisfaction, usability and local tolerability by patients, physicians and study nurses of two subcutaneously administered methotrexate (MTX) formulations of different concentrations.Methods:This was an open-label, comparative, within-patient controlled, multicentre study of 132 patients with rheumatoid arthritis (RA). MTX treatment consisted of 20 mg/week administered as a medium-concentration formulation (MC) (2.0 ml of 10 mg/ml solution in prefilled syringe; separate needle) compared to a novel high-concentration formulation (HC) (0.4 ml of 50 mg/ml in prefilled syringe; pre-attached needle). Each treatment was given for three weeks. Questionnaires and visual analogue scales were used to measure outcomes.Results:At the end of the study, 93% of the patients preferred HC over MC as further treatment. Overall assessment of HC was “good” or “very good” in 90.6% vs 34.4% in MC-treated patients. Physician’s and patients global assessment of syringe usability showed highly statistically significant differences (P < 0.0001) in favour of HC. Overall assessment by study nurses’ and investigators’ was “good” (18.8%) or “very good” (81.2%) for HC and “good” in 31.3% or “very good” in 12.5% for MC, and no preference in 50%. Local tolerability improved slightly also with HC.Conclusions:The total smaller volume of administered drug and the improved usability of a pre-attached needle in combination with a smaller prefilled syringe resulted in preference of the patients of HC over MC. The slightly improved local tolerability may also have added to this preference. This assessment was confirmed by similar assessments made by healthcare professionals.Eudra-CT number: 2007-003591-19.

Gender-specific prolactin response to antipsychotic treatments with risperidone and olanzapine and its relationship to drug concentrations in patients with acutely exacerbated schizophrenia

Hyperprolactinemia is a frequent consequence of treatment with antipsychotic agents, partially because the prolactin response to antipsychotics is related to dopamine blockade. Recent studies have suggested that the prolactin response to olanzapine is weaker than that to risperidone. Thus, we studied the effects of various factors on the elevated plasma prolactin levels caused by these medications. The subjects were 94 patients with acutely exacerbated schizophrenia (46 males, 48 females). For four weeks, they received 6 mg of risperidone and 20 mg of olanzapine daily. Plasma samples were collected before the medications were given and 12 h after the bedtime dosing each week. Treatment with either risperidone or olanzapine boosted plasma prolactin levels above baseline in both males and females. Prolactin levels were significantly higher in females than in males at all sampling points in both treatments. Risperidone increased prolactin significantly more than did olanzapine in both males and females. Delta prolactin (prolactin level at four weeks minus the baseline prolactin level) during olanzapine treatment significantly correlated with olanzapine concentration at 4th week ( r = − 0.518, p < 0.01) only in males. Multiple regression analyses showed that delta prolactin during risperidone was significantly correlated with gender ( p < 0.001) and age ( p < 0.05) and that delta prolactin during olanzapine significantly correlated with gender ( p < 0.001) and drug concentration ( p < 0.01). The present study suggests that the predominant factors influencing hyperprolactinemia are young female for risperidone treatment, and being female and lower drug concentration as a predictor for hyperprolactinemia under olanzapine.

Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock

IntroductionAltered pharmacokinetics (PK) in critically ill patients can result in insufficient serum β-lactam concentrations when standard dosages are administered. Previous studies on β-lactam PK have generally excluded the most severely ill patients, or were conducted during the steady-state period of treatment. The aim of our study was to determine whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem would result in adequate serum drug concentrations in patients with severe sepsis and septic shock.MethodsOpen, prospective, multicenter study in four Belgian intensive care units. All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom treatment with the study drugs was indicated, were included. Serum concentrations of the antibiotics were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5 and 6 or 8 hours after administration.Results80 patients were treated with piperacillin-tazobactam (n = 27), ceftazidime (n = 18), cefepime (n = 19) or meropenem (n = 16). Serum concentrations remained above 4 times the minimal inhibitory concentration (T > 4 × MIC), corresponding to the clinical breakpoint for Pseudomonas aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for 57% of the dosage interval for meropenem (target MIC = 8 μg/mL), 45% for ceftazidime (MIC = 32 μg/mL), 34% for cefepime (MIC = 32 μg/mL), and 33% for piperacillin-tazobactam (MIC = 64 μg/mL). The number of patients who attained the target PK profile was 12/16 for meropenem (75%), 5/18 for ceftazidime (28%), 3/19 (16%) for cefepime, and 12/27 (44%) for piperacillin-tazobactam.ConclusionsSerum concentrations of the antibiotic after the first dose were acceptable only for meropenem. Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime may, therefore, be insufficient to empirically cover less susceptible pathogens in the early phase of severe sepsis and septic shock.

An HPLC-PDA Method for the Simultaneous Quantification of the HIV Integrase Inhibitor Raltegravir, the New Nonnucleoside Reverse Transcriptase Inhibitor Etravirine, and 11 Other Antiretroviral Agents in the Plasma of HIV-Infected Patients

A new method using high-performance liquid chromatography coupled with photo diode array detection was developed and validated for the quantification of plasma concentrations of the human immunodeficiency syndrome integrase inhibitor raltegravir (RGV), the new nonnucleoside reverse transcriptase inhibitor etravirine (ETV), and 11 other antiretroviral agents: ritonavir, atazanavir, lopinavir, nevirapine, efavirenz, saquinavir, indinavir, nelfinavir, and its metabolite M-8, amprenavir, and darunavir. A simple solid phase extraction procedure was applied to 500 microL aliquots of plasma, and chromatographic separation of the drugs and internal standard (quinoxaline) was achieved with a gradient (acetonitrile and phosphate buffer) on an C-18 reverse-phase analytical column with a 28-minute analytical run time. Calibration curves were optimized according to expected ranges of drug concentrations in patients, and the coefficient of determination (r) was higher than 0.998 for all analytes. Mean intraday and interday precisions (percent relative SD) for all compounds were 3.67% and 6.39%, respectively, and mean accuracy (percent deviation from nominal concentration) was -1.17%. Extraction recovery ranged within 75% and 83% for all drugs analyzed. The solid phase extraction and high-performance liquid chromatography coupled with photo diode array method described allow a specific, sensitive, and reliable simultaneous determination of RGV, ETV, and 11 antiretroviral agents in plasma by a single assay. Good extraction efficiency and low limit of quantification make this a suitable method for use in clinical trials and for therapeutic drug monitoring of RGV, protease inhibitors, and nonnucleoside reverse transcriptase inhibitors, including ETV.

HPLC–MS method for the simultaneous quantification of the new HIV protease inhibitor darunavir, and 11 other antiretroviral agents in plasma of HIV-infected patients

A new method using high performance liquid chromatography coupled with electrospray mass spectrometry (HPLC–MS) was developed and validated, for the quantification of plasma concentration of the new protease inhibitors darunavir (DRV) and other 11 antiretroviral agents (ritonavir, amprenavir, atazanavir, lopinavir, saquinavir, indinavir, nelfinavir and its metabolite M-8, nevirapine, efavirenz and tipranavir). A simple protein precipitation extraction procedure was applied on 50 μl of plasma aliquots and chromatographic separation of drugs and Internal Standard (quinoxaline) was achieved with a gradient (acetonitrile and water with formic acid 0.05%) on an C-18 reverse phase analytical column with 25 min of analytical run. Calibration curves were optimised according to expected ranges of drug concentrations in patients, and correlation coefficient ( r 2) was higher than 0.998 for all analytes. Mean intra- and inter-day precision (relative standard deviation %) for all compounds were 8.4 and 8.3%, respectively, and mean accuracy (% of deviation from nominal level) was 3.9%. Extraction recovery ranged within 93 and 105% for all drugs analysed. This novel HPLC–MS methodology allows a specific, sensitive and reliable determination of DRV and 11 other antiretrovirals. In our hand, it was used to measure DRV and ritonavir plasma concentration in HIV-positive patients, and it is now successfully applied for routine therapeutic drug monitoring and pharmacokinetics studies.

Electrospray tandem mass spectroscopic characterisation of 18 antiretroviral drugs and simultaneous quantification of 12 antiretrovirals in plasma

The determination of antiretroviral drug concentrations in patients treated with highly active antiretroviral therapy (HAART) is an essential part of optimum patient management because of the multitude of pharmacokinetic drug interactions between these drugs and the risk of treatment failure or viral resistance if therapeutic concentrations are not reached. Currently, 21 different antiretrovirals are used in various combinations rendering therapeutic drug monitoring a laborious task. We therefore aimed to simultaneously determine as many antiretrovirals as possible using triple quadrupole mass spectroscopy with electrospray ionisation. For this purpose, spectra and fragmentation patterns of the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, the non-nucleoside reverse transcriptase inhibitors delavirdine, efavirenz, and nevirapine, the nucleoside reverse transcription inhibitors abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine, and zidovudine, and the nucleotide reverse transcriptase inhibitor tenofovir were evaluated. A bioanalytical method to determine all protease and non-nucleoside reverse transcriptase inhibitors, and zalcitabine and zidovudine concentrations in biological matrices was developed. Samples were prepared by protein precipitation with methanol after addition of three different internal standards. Antiretrovirals were separated by high-performance liquid chromatography on a Nucleosil C18-100 Nautilus column using a gradient of 20 mM ammonium acetate including 0.1% aqueous acetic acid and acetonitrile and detected by electrospray ionisation/tandem mass spectrometry in the negative (efavirenz, stavudine, zidovudine) or positive ionisation mode (all other compounds). The bioanalytical method was successfully validated according to FDA guidelines and applied to plasma and cerebrospinal fluid samples of patients treated for acquired immunodeficiency syndrome (AIDS).

Simplified Means of Evaluating Drug Concentrations in Patients' Blood Using Microsoft Excel at a Community Pharmacy

Using Microsoft Excel®,we explained in simple terms how the times of taking drugs are determined to patients at a pharmacy counter,in the case of medicines for children.We highlighted the change in drug concentrations with time using pharmacokinetics parameters,such as time of peak concentration,half-life,and area under the blood concentration-time curve,whose values were indicated in the interview-form.Prediction of the blood drug concentration curve was based on the one-compartment absorption model.We found that various drugs,such as aciclovir (Astric® dry syrup),oseltamivir phosphate (Tamiflu® dry syrup),clarithromycin (Clarith® dry syrup),cefditoren pivoxil (Meiact MS® fine granules),oxatomide (Celtect® dry syrup) and procaterol hydrochloride (Meptin® dry syrup),had characteristic concentration patterns that could be understood visually.We also noted that the indices provided by our simple evaluation using Microsoft Excel® enabled drug concentrations in blood-time profiles to be compared visually in the case of patients complying with medication schedules and those not complying e.g.in the case that schedules are modified,the patient misses taking medicine or takes more than 1 dose at once.It was also possible to examine the relationship between the predicted blood concentration patterns of drugs and their efficacy or safety for each medicine.This technique would be useful means of helping pharmacists to fully realize their role in the community pharmacy.

Pharmacodynamics not likely to appear in antimicrobial labeling soon

Despite the potential usefulness of pharmacodynamic models, clinicians should not soon expect to routinely see FDA-vetted information on how antimicrobial drug concentrations in patients relate to microbiologic and clinical outcomes, experts said at a recent symposium on pharmacodynamics. “The

Determinants of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Pharmacokinetics in a Cohort of Tuberculosis Patients

Evaluation of sources of pharmacokinetic variation can facilitate optimization of tuberculosis treatment regimens by identification of avoidable sources of variation and of risk factors for low or high drug concentrations in patients. Our objective was to describe the pharmacokinetics of rifampin, isoniazid, pyrazinamide, and ethambutol in a cohort of tuberculosis patients established on first-line treatment regimens and to evaluate the determinants of pharmacokinetic variation. Plasma concentration-time profiles were determined for each of the drugs in 142 patients with drug-sensitive pulmonary tuberculosis after 2 months of daily treatment in hospital. Pharmacokinetic measures were described by noncompartmental analysis. Multiple linear regression was used to evaluate the patient and the treatment factors associated with variation of the area under the concentration-time curve from 0 to 8 h. Several factors independently associated with variations in antituberculosis drug concentrations were identified: human immunodeficiency virus infection was associated with 39% and 27% reductions for rifampin and ethambutol, respectively; formulation factors were determinants of rifampin and isoniazid bioavailability; female patients had increased rifampin and isoniazid concentrations but reduced ethambutol concentrations; older patients had higher levels of isoniazid and ethambutol; patients with a history of previous antituberculosis treatment had lower ethambutol concentrations; and the dose per kilogram of body weight was associated with the concentrations of all four agents. Further studies are required to assess the implications of variations in antituberculosis drug concentrations for efficacy and safety before decisions are made to change the dosing strategy in patients at risk.

Severe Hyperglycemia During Renally Adjusted Gatifloxacin Therapy

To report a case of severe hyperglycemia in a nondiabetic patient receiving gatifloxacin that was properly dosed based on renal function. A 65-year-old nondiabetic female with progressive renal dysfunction was admitted for severe hyperglycemia. The patient had received 9 days of a 10-day course of renally adjusted therapy with gatifloxacin 200 mg/day for bronchitis. Her blood glucose level on admission was 1121 mg/dL, at which point the gatifloxacin was discontinued. After several days of intensive insulin therapy, the blood glucose levels returned to normal, and the patient was subsequently discharged. Gatifloxacin-induced hyperglycemia has been reported in the literature, but based on a MEDLINE search (1966-December 2004), no such cases were found in a nondiabetic patient receiving the proper gatifloxacin dose, adjusted for degree of renal insufficiency. The available case reports seem to suggest the increase in blood glucose concentrations could have been precipitated by high drug concentrations in patients not receiving the renally adjusted dose or in those with preexisting, undiagnosed diabetes. A definite mechanism of action for gatifloxacin-induced hyperglycemia is not known. The Naranjo probability scale revealed a probable adverse reaction of hyperglycemia associated with gatifloxacin therapy. Healthcare professionals should be more aware of the possible development of hyperglycemia in all patients taking gatifloxacin, including those who are not diabetic and those receiving appropriately reduced doses for renal dysfunction.

Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study

HIV-1-infected patients vary considerably by their response to antiretroviral treatment, drug concentrations in plasma, toxic events, and rate of immune recovery. This variability could have a genetic basis. We did a pharmacogenetics study to analyse the association between response to antiretroviral treatment and allelic variants of several genes. In 123 patients, we did PCR analyses of the gene for the multidrug-resistance transporter (MDR1), which codes for P-glycoprotein, of genes coding for isoenzymes of cytochrome P450, CYP3A4, CYP3A5, CYP2D6, and CYP2C19, and of the gene for the chemokine receptor CCR5. We measured concentrations in plasma of the antiretroviral agents efavirenz and nelfinavir by high-performance liquid-chromatography, and measured levels of P-glycoprotein expression, CD4-cell count, and HIV-1 viraemia. Median drug concentrations in patients with the MDR1 3435 TT, CT, and CC genotypes were at the 30th, 50th, and 75th percentiles, respectively (p=0.0001). In patients with CYP2D6 extensive-metaboliser or poor-metaboliser alleles, median drug concentrations were at percentiles 45 and 62.5, respectively (p=0.04). Patients with the MDR1 TT genotype 6 months after starting treatment had a greater rise in CD4-cell count (257 cells/microL) than patients with the CT (165 cells/microL) and CC (121 cells/microL) genotype (p=0.0048), and the best recovery of naïve CD4-cells. The polymorphism MDR1 3435 C/T predicts immune recovery after initiation of antiretroviral treatment. This finding suggests that P-glycoprotein has an important role in admittance of antiretroviral drugs to restricted compartments in vivo.

Iron distribution in cancer cells following doxorubicin exposure using proton and X-ray synchrotron radiation microprobes

Chemical studies have shown that doxorubicin, a well-established anticancer agent, is a powerful iron chelator and the resultant iron–drug complex is an efficient catalyst of the conversion of hydrogen peroxide to the highly reactive hydroxyl radical. However, the intracellular complexation of doxorubicin with iron is still debated. Using nuclear microprobe analysis (NMPA), we previously observed in human ovarian cancer cells exposed to 20 μM iodo-doxorubicin (IDX) that iodine and iron cellular distributions were spatially correlated, suggesting a mechanism of intracellular iron chelation by the anthracycline compound. Because maximal plasma drug concentrations in patients are expected to be around 5 μM, NMPA and X-ray absorption near edge spectroscopy (XANES) experiments for iron speciation analysis were performed on cultured cells exposed to pharmacological doses of 2 μM IDX or doxorubicin.

Accuracy of measured vancomycin serum concentrations in patients with end-stage renal disease.

To review information related to the accuracy of vancomycin serum drug concentrations in patients with end-stage renal disease, focusing on available assays and mechanisms of cross-reactivity. Primary and review articles identified from a MEDLINE search (January 1980-June 1999) and through secondary sources. All articles identified were evaluated, and all relevant information was included in this review. Falsely elevated vancomycin serum concentrations may occur in patients with renal dysfunction. The underlying mechanism is due to the formation and accumulation of a pseudo-metabolite, the vancomycin crystalline degradation product (CDP). Vancomycin is converted to CDP when exposed to heat, including normal body temperature. Because the molecular structures of CDP and vancomycin are similar, both molecules are detected by polyclonal immunoassay systems used in clinical laboratories. This cross-reactivity leads to falsely elevated serum vancomycin concentrations in excess of 50-70%. Such large assay inaccuracies may result in improper dosage adjustments and therapeutic failures. A monoclonal immunoassay system has been developed that does not significantly cross-react with CDP. To appropriately interpret laboratory results, it is essential for clinicians to be aware of the vancomycin-CDP cross-reactivity problem and to be familiar with the specific assay used to measure vancomycin concentrations in patients with renal dysfunction.

Elevated free phenytoin and free valproic acid concentrations in sera of patients infected with human immunodeficiency virus.

Seizures are common in patients infected with human immunodeficiency virus (HIV). Phenytoin and valproic acid are common anticonvulsants, and both drugs are strongly bound to serum albumin. Because patients infected with HIV are often on polytherapy, using homeopathic medicines, and may also have hypoalbuminemia, elevated free drug concentrations may occur in these patients. The authors prepared one serum pool from patients infected with HIV but receiving no bactrim and the other pool from HIV patients receiving bactrim. They supplemented both HIV pools and normal pool (diluted with 0.9% saline to mimic albumin concentration of HIV pools) with a known concentration of phenytoin or valproic acid. After incubation at 37 degrees C for 3 hours, they measured free phenytoin and free valproic acid concentrations in the protein free ultrafiltrates using fluorescence polarization immunoassays. The total drug concentrations in original sera were measured by microparticle enzyme immunoassays. None of the patients had any significant liver or renal disease. The aliquots of HIV pools and normal pool were supplemented with the same concentration of phenytoin or valproic acid. The concentration of free phenytoin and free valproic acid were significantly elevated in patients with HIV (mean = 2.52, SD = 0.11 micrograms/ml for phenytoin; mean = 41.5, SD = 1.5 micrograms/ml for valproate) compared to controls (mean = 1.50, SD = 0.0 7 micrograms/ml for phenytoin; mean = 19.9, SD = 0.5 micrograms/ml for valproate). The concentrations of both free phenytoin and valproic acid were further elevated in patients prepared in the HIV pool who were receiving bactrim (mean = 2.81, SD = 0.09 micrograms/ml for phenytoin; mean = 44.0, SD = 1.1 micrograms/ml for valproate), but when normal serum pool was supplemented with 4.4 mg/dl of bactrim (concentration of bactrim in HIV pool) and supplemented with the same concentration of phenytoin or valproic acid, the observed free concentrations were much lower (mean = 1.65, SD = 0.05 micrograms/ml for phenytoin; mean = 26.1, SD = 1.4 micrograms/ml for valproate). This indicates that hypoalbuminemia and bactrim concentrations do not account for the observed free drug concentrations in patients with HIV. The authors also observed elevated free phenytoin and valproic acid in sera from three individual patients with AIDS compared to normals (normal serum diluted with 0.9% saline to mimic the albumin concentration of serum collected from a patient with HIV and then both specimens supplemented with the same concentration of phenytoin or valproic acid.

Predictive performance of population pharmacokinetic parameters of tianeptine as applied to plasma concentrations from a post-marketing study.

The predictive ability of population pharmacokinetic parameters of tianeptine, obtained from a mixed effect analysis of pre-marketing pharmacokinetic studies, was evaluated using tianeptine plasma concentrations obtained during a large multi-center post-marketing surveillance study. The mean prediction error was 7.8 ng.ml-1 and the root mean square prediction error was 52.1 ng/ml when initial estimates of population pharmacokinetic parameters were used to predict drug concentrations in one half of the post-marketing data. When the population parameters were revised to reflect the data collected in the first half of the post-marketing study, the mean prediction error was reduced to -3.2 ng.ml-1 and the root mean square prediction error was reduced to 29.5 ng.ml-1. These results suggest that population pharmacokinetic parameters obtained from pre-marketing data may not accurately predict drug concentrations in patients receiving the drug in the post-marketing setting. Once the population parameters are updated to reflect data from the post-marketing period, the predictive ability of the data-base increases, but substantial variability in the prediction error remains.

Variability in the Oral Bioavailability of All-trans-Retinoic Acid

Orally administered all-trans-retinoic acid (all-trans-RA) can induce complete remission in a high proportion of patients with acute promyelocytic leukemia. A previous pharmacokinetic study in patients with acute promyelocytic leukemia raised the possibility that the absorption of orally administered all-trans-RA is a saturable process that would have significant clinical impact on dosing strategies. This study was specifically designed to examine the saturability of all-trans-RA absorption by measuring the effect of doubling the oral dose of all-trans-RA on plasma drug concentration in patients receiving long-term oral therapy. Six patients with solid tumors received oral doses of 10-mg gelatin capsules of all-trans-RA. Patients were studied on 2 consecutive days after they received 28 days of all-trans-RA administered as two daily 78-mg/m2 doses. The study assigned the patients to two groups. Three patients took a 156-mg/m2 dose on day 28 and a 78-mg/m2 dose on day 29; the other three patients took the lower dose on day 28 and the double dose on day 29. Blood samples for the determination of all-trans-RA plasma concentration were obtained at 30-minute intervals starting just prior to drug administration and continuing for a total of 7 hours. The plasma concentration of all-trans-RA was measured by high-performance liquid chromatography. Plasma concentrations following an oral dose of all-trans-RA were highly variable, with peak concentrations ranging from 0.07 to 1.2 microM for the 78-mg/m2 dose level. Doubling the dose from 78 to 156 mg/m2 increased plasma concentration in all six patients, but the increase was unpredictable and not related to dose, ranging from less than a 1.2-fold to more than a 10-fold increase. The current study does not support the hypothesis that the gastrointestinal absorption of all-trans-RA involves a saturable process but instead suggests that absorption is highly variable among patients. This wide interpatient variability suggests that pharmacokinetic drug monitoring may have an important role in the management of patients receiving all-trans-RA.

Action potential prolongation exhibits simple dose-dependence for sotalol, but reverse dose-dependence for quinidine and disopyramide: implications for proarrhythmia due to triggered activity.

Plasma drug concentrations in patients who develop torsade de pointes while receiving quinidine or disopyramide treatment have been reported to be usually in or below the therapeutic range, whereas patients developing the same complication during sotalol treatment usually have drug concentrations well above the therapeutic range. We wished to provide a cellular electrophysiologic rationale for this observation. Standard intracellular microelectrode techniques were used to record action potentials (APs) from canine Purkinje fibers at interstimulus intervals (ISI) of 1,000-6,000 ms, with and without three varying concentrations of quinidine, disopyramide, and sotalol. Cesium chloride 0.5 mM was added to reduce spontaneous diastolic depolarization. We observed a biphasic response in action potential duration (APD) to quinidine and disopyramide. Low concentrations tended to prolong APD, particularly at slower drive rates, whereas this effect tended to reverse as the concentration was increased. In contrast, sotalol produced a consistent, monophasic dose-dependent increase in APD across the therapeutic concentration range and well beyond it. We also observed an apparent increased likelihood of early afterdepolarizations (EADs), with or without triggered activity, at low concentrations of quinidine and disopyramide, with a trend toward reversal as the concentration was increased. We conclude that the biphasic dose response observed for APD with quinidine and disopyramide is due to the opposing effects of these agents on outward potassium and inward sodium currents and may cast some light on the clinical observation noted above. Sotalol on the other hand appears to produce EADs and triggered activity only at high concentrations.

Determination of nifedipine in plasma by a rapid capillary gas chromatographic method.

A rapid, specific and reliable gas chromatographic assay procedure for Nifedipine in plasma has been developed. With a single-step solvent extraction, and electron capture detection, the method is sensitive to 0.5 ng/mL of plasma and the standard curve is linear from 0.5 to 500 ng/mL. Samples are protected from light to prevent formation of photodecomposition products. The method has been used to monitor drug concentrations in patients receiving therapeutic doses.