Complex Pharmacokinetic Profile Research Articles

Severe Neutropenia in a Renal Transplant Patient Suggesting an Interaction Between Mycophenolate and Fenofibrate

To describe a patient in whom initiation of micronized fenofibrate precipitated mycophenolate induced neutropenia. A 57-year-old man was admitted to the hospital because of febrile neutropenia. He had undergone kidney transplantation seventeen years ago. The patient's immunosuppressive maintenance regimen consisted of mycophenolate mofetil (MMF) 500 mg three times a day, and meprednisone 4 mg daily. His medical history included, hypertension treated with losartan 50mg daily, and dyslipidemia treated with ezetimibe 10mg /simvastatin 20mg for four years (until 2 weeks before admission when micronized fenofibrate 200 mg per day was started because of persistently elevated triglycerides levels. On presentation temperature was 37.8°C and initial laboratory tests showed 3130 White Blood Cell Count(WBC)/μL with neutropenia (absolute neutrophil count (ANC) 313/μL) Fenofibrate and mycophenolate mofetil were discontinued, piperacillin tazobactam 4.5gr three times a day and granulocyte stimulation factor 300 μg/day were started. Three days after admission WBC was 7280/μL, neutrophils: 22%, ANC: 1160/mm(3). Mycophenolate mofetil was restarted and granulocyte stimulation factor was discontinued. One month after discharge his WBC was 4480/μL and ANC 1926/μL. The initiation of fenofibrate in a patient on stable and therapeutic doses of mycophenolate may have precipitated mycophenolate induced neutropenia, a well described, dose dependent phenomenon. Mycophenolic acid (MPA) displays a complex pharmacokinetic profile susceptible to potential significant interactions with fenofibrate. Since approximately 99% of MPA and fenofibrate bind to albumin, displacement may occur, leading to increased free MPA. Second competition of fenofibric acid for UGT1A9 an enzyme implicated in conjugation of MPA may have decreased its metabolism. The combination of these two effects may increase the risk of dose dependent neutropenia. Using the Interaction Probability Scale (DIPS), the interaction was designated as probable. Until further evidence is available, when fenofibrate is started in a renal transplant patient on mycophenolate careful monitoring should be considered to avoid potentially fatal complications.

The Influence of Sparse Data Sampling on Population Pharmacokinetics: A Post Hoc Analysis of a Pharmacokinetic Study of Morphine in Healthy Volunteers

BackgroundIntensive sampling of patients for drugs with complex pharmacokinetic profiles is difficult to perform in the clinic or hospitalized patient setting. We seek to address whether sparse sampling can obtain pharmacokinetic parameter values similar to those with traditional modeling from a post hoc analysis of 2 previous clinical trials. ObjectiveThis study investigated whether population-guided, sparse-sampling pharmacokinetic analysis of morphine in 14 healthy volunteers allowed for optimal characterization of concentration-time profiles for a validation population of 5 young male patients receiving morphine. MethodsData were analyzed using nonparametric adaptive grid (NPAG) population modeling to investigate optimal compartmental structure and the influence of sparse sampling (ie, 9 versus 3 samples per subject) on parameter identification. These results were compared with traditional standard 2-stage (STS) pharmacokinetic modeling. The coefficients of determination (R2), mean error (ME), and root-mean-square error were used to assess the predictive performance of the various sampling models against a validation population. ResultsSeventy-nine percent of the healthy volunteers were male, with a mean age of 36 (17) years and a mean weight of 68 (10) kg. NPAG modeling identified that intravenous morphine was best represented by a 3-compartment pharmacokinetic profile and that sparse sampling with a least 3 blood samples per subject resulted in virtually identical measures of central tendency as the more intensively sampled dataset. A validation cohort of 5 male patients undergoing elective surgery had a mean age of 26 (4) years and a mean weight of 80 (13) kg. Using mean parameter estimates generated from sparse sampling and the 3-compartment model structure, simulated profiles were compared against measured concentrations in this validation cohort. Sparse sampling using NPAG achieved similar values of predictive performance as mean parameter values from the more intensively sampled, with an ME of −1.0 ng/mL and precision of 26.2 ng/mL compared with 0.76 ng/mL and 25.8 ng/mL, respectively. Traditional (STS) modeling techniques resulted in the greatest degree of underprediction within the validation group (ME = 4.43 versus 0.76 ng/mL, STS and NPAG-9, respectively; P < 0.0001). ConclusionsThis post hoc analysis suggests that intensive sampling for discerning complex, 3-compartment pharmacokinetic models, such as morphine, may not be necessary. Sparse sampling achieved accurate model structure recognition and parameter identification for predicting concentrations of very complex drug-dosage regimens.

Digoxin: Clinical Highlights

Digoxin is the oldest cardiac medication used in contemporary medicine. With a complex pharmacokinetic profile and narrow therapeutic index, its use in managing patients with atrial arrhythmias or heart failure can present a challenge to today's clinicians. Digoxin dosing based on patient-specific factors such as age, lean body weight, and renal function will allow practitioners to minimize drug toxicity while maintaining clinical efficacy. The ability to recognize digoxin overdose, which can manifest in both the acute and chronic settings, helps guide the appropriate dosing of digoxin immune globulins to reverse toxicity. Understanding this unique medication is essential for clinicians to ensure digoxin is used safely and effectively in practice.

Quality of anticoagulation control in atrial fibrillation

Overwhelming evidence lends supports to the use of oral anticoagulants as thromboprophylaxis in patients with atrial fibrillation, traditionally with vitamin K antagonists, such as warfarin (to maintain the international normalised ratio [INR] to 2·0–3·0)1 but more recently with the novel oral anticoagulant dabigatran.2 The development of new oral anticoagulants grew from the inherent difficulties associated with vitamin K antagonists, particularly their complex pharmacokinetic profile: narrow therapeutic range (INR 2·0–3·0) needing regular monitoring; slow onset and offset of action; several interactions with food, alcohol, and drugs; and potential ethnic, genetic, and age-related variations in dose response.

Understanding the clinical pharmacokinetics of a GABAA partial agonist by application of in vitro tools

4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4-methylaminomethyl-phenyl)-amide (1), developed for general anxiety disorder, was discontinued from clinical development due to unsuitable oral pharmacokinetics.In humans, (1) demonstrated an unacceptable high apparent oral clearance (Clp/F) that also demonstrated a supraproportional dose-exposure relationship. Secondary peaks in the plasma concentration-time profile suggested possible enterohepatic recirculation of (1). A combination of in vitro mechanistic tools was applied to better understand the processes underlying these complex clinical pharmacokinetic profiles of (1).In metabolism experiments, (1) was shown to be a substrate of monoamine oxidase A (MAO-A) as well as being metabolized by cytochrome P450. The former appeared to be a high KM process with a high capacity, while the latter showed saturation between 1 and 10 μM, consistent with the supraproportional dose-exposure relationship.In a sandwich-cultured hepatocyte model, (1) was shown to be a substrate for both uptake and efflux into the canicular space, which is consistent with the observation of pharmacokinetics suggestive of enterohepatic recirculation. Finally, in human epithelial colon adenocarcinoma cell line (Caco-2) and Madin-Darby canine kidney cells transwell flux experiments, (1) was shown to have relatively low permeability and a basolateral-to-apical flux ratio consistent with the activity of P-glycoprotein.In combination, a compounding of the contributions of MAO-A, hepatic uptake and efflux transporters, and P-glycoprotein to the disposition of (1) may underlie the low oral exposure, saturable clearance, and aberrant concentration versus time profiles observed for this compound in humans.

Characterization of human cytochrome P450 isoforms involved in the metabolism of 7-epi-paclitaxel

The C-7 chiral centre in paclitaxel is subject to epimerization under physiological conditions, thus making 7-epi-paclitaxel as the principal degradant. This study was designed to characterize the cytochrome P450 (CYP) enzymes involved in 7-epi-paclitaxel metabolism, and to examine possible metabolic interactions that this C-7 epimer may have with paclitaxel.In human liver microsomes, 7-epi-paclitaxel was oxidized to two monohydroxylated metabolites while the metabolic sites occurred at the C-13 side-chain for M-1 and taxane core ring for M-2. A combination of correlation analysis, chemical inhibition studies, assays with recombinant CYPs, and enzyme kinetics indicated that M-1 was generated predominantly by CYP3A4 and M-2 by CYP2C8. Co-incubation of 7-epi-paclitaxel with paclitaxel in human liver microsomes resulted in potent inhibition of 6α-hydroxypaclitaxel formation (IC50 = 2.1 ± 0.2 μM), thus decreasing the metabolic elimination of paclitaxel.In conclusion, both CYP3A4 and CYP2C8 play a major role in biotransformation of 7-epi-paclitaxel in human liver microsomes. The existence of epimeric interactions between paclitaxel and its degradant might be a noteworthy factor resulting in the complex pharmacokinetic profile of paclitaxel.

Warfarin and its interactions with foods, herbs and other dietary supplements

Despite its complex pharmacokinetic and pharmacodynamic profile, warfarin is still one of the most widely used oral anticoagulant agents. Attaining optimal anticoagulation with this agent is clinically challenging in view of its many food and drug interactions. Inappropriate anticoagulation control can expose patients to an increased risk of bleeding or thromboembolic complications, due to over and underanticoagulation, respectively. Fluctuations in dietary vitamin K intake can have a significant effect on the degree of anticoagulation in patients treated with warfarin. In addition, the explosion in use of various dietary supplements and herbal products can lead to undesired outcomes on anticoagulant levels. The aim of this review is to discuss the scope and the potential clinical impact of the most commonly reported food, dietary supplement and herbal interactions with warfarin therapy. Practical steps for patients and providers to minimise these interactions are highlighted.

Extended-release carbamazepine for acute bipolar mania: A review

In December 2004, an extended-release capsule formulation of carbamazepine was approved by the U.S. Food and Drug Administration for the treatment of acute manic or mixed episodes associated with bipolar I disorder. This formulation allows twice-daily dosing and minimizes plasma carbamazepine fluctuations. The efficacy, safety and tolerability of the product were demonstrated with two pivotal randomized, placebo-controlled, double-blind monotherapy trials. These studies showed efficacy in bipolar I mania in patients with acute manic or mixed episodes. Pooled post hoc analyses documented a significant onset of effect within seven days, an incremental response of about 25% over placebo and a moderate effect size of 0.61 with no treatment-emergent depression. Carbamazepine's mode of action in mania is unknown, but a variety of effects on receptors, neurotransmitters, ion channels and binding sites have been documented. It has a complex pharmacokinetic profile due to autoinduction and a long-acting active metabolite. Carbamazepine's most frequent adverse events comprise dizziness, somnolence, nausea and vomiting, although these tend to diminish over time. It is effectively weight neutral and can provide an acceptable and efficacious treatment option for bipolar I mania.

Concomitant drug, dietary, and lifestyle issues in patients with atrial fibrillation receiving anticoagulation therapy for stroke prophylaxis

Atrial fibrillation is a common cardiac arrhythmia and the leading risk factor for stroke. In those at moderate to high risk of stroke, oral anticoagulation therapy with warfarin (a vitamin K antagonist) significantly reduces not only the frequency of such events but also their severity and the associated risk of death. However, achieving optimal anticoagulation with this agent is clinically challenging in view of its complex pharmacokinetic and pharmacodynamic profile. In this regard, concomitant drug therapy (both prescription and over-the-counter medications, including herbal products, vitamins, and various nutritional supplements), along with alcohol intake, dietary factors, and changes in lifestyle, can significantly affect anticoagulation control and thereby expose patients to the risk of bleeding or thromboembolic complications (due to over- and underanticoagulation, respectively). Therefore, it is recommended that intensified monitoring of anticoagulation be performed at initiation and discontinuation of concomitant drug therapy, and in the case of significant dietary and lifestyle changes. Moreover, many patients receive inadequate education and are unaware of such risks and their implications, highlighting the need for better awareness and education on this important aspect of anticoagulation therapy.

Medication errors: considerations for nurse prescribers

Medication errors continue to be a problem involving patients in both primary and secondary care settings. Current evidence suggests that medication errors are costly and increasing (Dobrzanski et al, 2002). For this reason, the Department of Health (2001) aims to reduce the incidence of medication errors by approximately 40% by 2005. Prescribing medication is a relatively new task for nurse prescribers and because of this, vigilance with regard to prescription writing standards is required in order to avoid mistakes in the writing of prescriptions. Nurse prescribers need to maintain the currency of their knowledge in applied pharmacology and therapeutics in order to prevent prescribing errors that involve medications with complex pharmacokinetic and pharmacodynamic profiles.

Pharmacokinetics of recombinant human leukemia inhibitory factor in sheep.

The pharmacokinetics of recombinant human leukemia inhibitory factor (rhLIF) were investigated following i.v. and s.c. administration of a wide range of dose levels. Parallel studies were conducted where single i.v. bolus doses of 12.5, 25, 100, 250, 500, or 750 microg/kg rhLIF (n = 2) or s.c. doses of 10, 20, or 50 microg/kg rhLIF (n = 4) were administered to sheep. Blood samples were collected for up to 24 h postdosing, and the plasma concentrations of rhLIF were analyzed by enzyme-linked immunosorbent assay. Noncompartmental analysis demonstrated an increase in the terminal elimination half-life (from 0.27 to 2.29 h) and a decrease in systemic clearance (from 5.18 to 1.09 ml/min/kg) with increasing i.v. doses of rhLIF, suggesting nonlinear pharmacokinetic behavior. A greater than proportional increase in the area under the plasma concentration-time curve with dose also indicated significantly nonlinear pharmacokinetics after s.c. administration. A mechanistic compartmental model was developed to characterize the pharmacokinetics of rhLIF. The key feature of the model accounting for the nonlinear pharmacokinetic behavior of rhLIF was high-affinity, saturable receptor binding and subsequent cellular internalization and degradation. The apparent total density of LIF cell surface receptors and receptor turnover dynamics were included in the model, along with nonspecific binding and linear elimination from the systemic circulation. The absorption of rhLIF from the s.c. injection site into the systemic circulation was characterized by a first-order absorption process via a delay compartment. The proposed model satisfactorily captured the complex pharmacokinetic profiles of rhLIF following both i.v. and s.c. administration.

Dose-related pharmacokinetics and pharmacodynamics of valproate in the elderly.

Valproate exhibits a complex pharmacokinetic profile due to concentration-dependent protein binding and clearance. It has been shown that the protein binding of valproate decreases as the serum concentration increases in a young adult population. Furthermore, the percentage of protein binding is lower in the elderly compared with young adults at comparable low therapeutic serum concentrations. The extent of valproate protein binding at higher concentrations in the elderly has not been described. Studies conducted in the elderly have found unbound valproate clearance to be decreased compared with younger adults, although these changes in clearance have not been evaluated at higher therapeutic serum concentrations. We evaluated the pharmacokinetics of valproate (protein binding and clearance) across a wide dosage range in the elderly and measured the impact of this on drug-related side effects using a single-blind within-subject study design in 6 healthy elderly volunteers (aged 65-76 years). Steady-state total and unbound serum valproate concentrations were assessed at 3 doses: 500, 1000, and 1500 mg/d. As doses and valproate serum concentrations increased, the unbound fraction (10.0%, 13.0%, 17.4%) and total clearance (4.8, 6.0, 6.7 mL/h/kg) increased, respectively. Unbound clearance decreased (49.4, 45.8, 39.4 mL/h/kg) with increasing valproate serum concentrations. Drug-induced CNS effects and nausea severity scores correlated with total and unbound serum valproate concentrations. Significant dose-dependent changes in valproate pharmacokinetics were observed in the elderly.

Levosimendan: a new era for inodilator therapy for heart failure?

Levosimendan is a new inotropic and vasodilator agent. The inotropic effect is mediated by calcium concentration-dependent conformational changes in troponin C during systole leading to sensitization of the contractile apparatus to calcium ions. The vasodilator effect is mediated by opening potassium channels on vascular smooth muscle. It has a complex pharmacokinetic profile, with a long-acting metabolite that has hemodynamic effects persisting for approximately 1 week. Although it is absorbed orally, it has been developed only for intravenous use thus far. The hemodynamic effects are not reduced and may be enhanced in the presence of beta-blockers, possibly an important attribute when dealing with exacerbation of heart failure caused by or in the presence of beta-blockers. More patients with heart failure have participated in randomized controlled trials of levosimendan than of any other intravenous inotropic agent. Experience with its use after cardiac surgery is limited. Preliminary observations suggest that hemodynamic changes are associated with symptomatic benefit and a reduction in morbidity and mortality in patients with severe heart failure caused by left ventricular systolic dysfunction, compared with placebo in one study and dobutamine in another. Levosimendan may be the first inotropic agent that it is both safe and effective in altering clinical outcomes relevant for patients. Part of this benefit may be achieved because levosimendan allows other inotropic agents that may have adverse effects on patient outcome to be avoided. Further research is required to confirm whether levosimendan reduces mortality and morbidity compared with a placebo and when administered repetitively. If it does, it may become routine therapy for the treatment of severe heart failure.

The use of other drugs to allow a lower dosage of cyclosporin to be used. Therapeutic and pharmacoeconomic considerations.

Since its discovery in 1970, and introduction into clinical practice in 1978, cyclosporin has become the most important immunosuppressive drug used to prevent organ transplant rejection. This has been achieved by virtue of the improved graft survival rates and adverse effect profiles in patients when compared with that of the older agents. Cyclosporin is substantially more expensive (both to provide and to monitor) however, and the magnitude of these costs may preclude its use, particularly where the transplant recipient is required to pay. Cyclosporin has a complex pharmacokinetic profile with poor absorption, extensive metabolism to more than 30 metabolites and considerable inter- and intrapatient variability. Many transplant centres routinely use drugs ("cyclosporin-sparing agents') to allow a reduction in the dosage of cyclosporin while maintaining therapeutic blood cyclosporin concentrations. The use of a second drug to affect the pharmacokinetic profile of a primary drug is not new, but the use of cyclosporin-sparing agents is a departure from previous practices in that this coprescription is primarily for economic reasons. The decision to use these agents (and the choice of agent) is based upon economic and other factors including the extent of the cyclosporin-sparing effect, the potential for additional therapeutic benefit and/or adverse effects. The coprescription of cyclosporin-sparing agents is ethically more acceptable where the transplant recipient is the economic beneficiary but where the savings accrue to a third party it is more difficult. Benefits to the community at large must be balanced against the risk of adverse effects to the patient. The use of cyclosporin-sparing agents may reduce compliance and hence, jeopardise transplant and/or recipient outcomes. The transplant recipient must be informed about the reasons for their use and advised to consult an experienced physician or pharmacist before altering the established drug regimen.

Separation of propafenone enantiomers by liquid chromatography with a chiral counter ion

Propafenone is a class Ic antiarrhythmic drug with complex pharmacological and pharmacokinetic profiles due to the existence of an asymmetric carbon that is only available as a racemic mixture. A liquid chromatographic method for the determination of propafenone enantiomers using N-benzyloxycarbonylglycyl- l-proline as the chiral selector in the mobile phase is described. Studies on the retention behaviour of both propafenone and propranolol (internal standard) enantiomers with different mobile phase compositions permitted the determination of the optimum conditions. The best resolution for propafenone enantiomers was 2.3. Application to plasma samples with a simple sample preparation is also presented. The method was linear up to 2500 ng/ml of racemic propafenone and the limit of detection was 100 ng/ml for each enantiomer.

Cyclosporine pharmacokinetics and blood level monitoring.

Although monitoring plasma or whole blood concentrations of cyclosporine has been promoted as a means of limiting toxicity while ensuring adequate immunosuppression, no consensus has been reached with regard to the assay, the specimen to be assayed, the frequency of monitoring, the therapeutic range, or even the necessity of monitoring cyclosporine concentrations. The failure to reach such a consensus can be attributed to a great extent to the complex pharmacokinetic profile of cyclosporine and the inconsistencies in the assay methodology and results used to generate is pharmacokinetic profile. This article places the subject of monitoring cyclosporine concentrations in perspective by reviewing the pharmacokinetics of cyclosporine, the assay methodology, and the published clinical experience with blood level monitoring.

Clinical pharmacokinetics of bretylium.

Bretylium is a class III antiarrhythmic agent which is used for the management of serious and refractory ventricular tachyarrhythmias. It exhibits a complex pharmacokinetic profile which is poorly understood. The drug is poorly absorbed following oral administration, and its oral bioavailability is in the region of 18 to 23%. Peak plasma concentrations occur at 1 to 9 hours after oral ingestion, and following oral doses of 5 mg/kg average 76 ng/ml, which is 28-fold lower than those achieved after equivalent intravenous doses. Approximately 75% of a bretylium dose is absorbed within 24 hours of intramuscular administration. Peak plasma concentrations occur at 30 to 90 minutes after intramuscular administration and range from 670 to 1500 ng/ml in subjects receiving 4 mg/kg. Bretylium is negligibly bound to plasma proteins (1-6%). Although drug tissue concentrations have not been reported in humans, high values for the apparent volume of distribution suggest extensive tissue binding. In animals, bretylium is progressively taken up by the myocardium over a period of 12 hours, and at 12 hours after bolus administration, myocardial concentrations exceed plasma concentrations 6 to 12 times. It is also avidly taken up by adrenergic nerves in animals. Bretylium is almost entirely cleared by the renal route and its total body clearance is closely correlated with renal clearance. Available data suggest that bretylium exhibits a complex pharmacokinetic profile which has been described by a 3-compartment model in subjects receiving intravenous dosing. The terminal elimination half-life ranges from 7 to 11 hours following oral, intramuscular and intravenous administration, and renal clearance is about 600 ml/min after intravenous administration.(ABSTRACT TRUNCATED AT 250 WORDS)