Massimo Baraldo

The influence of circadian rhythms on the kinetics of drugs in humans.

In clinical practice, it is important to consider circadian rhythms in pharmacokinetics and cell responses to therapy in order to design proper protocols for drug administration. Scientists have arrived at this conclusion after several experiments in animals and in humans have clearly demonstrated that all organisms are highly organised according to circadian rhythms. These temporal cycles influence different physiological functions and, consequently, can influence the pharmacokinetic phases of drugs. A drugs pharmacokinetics can be modified according to the time of drug administration. In fact, the circadian changes of > 100 different compounds have been documented. The results obtained have led several scientific societies to provide guidelines concerning the timing of drug dosing for anticancer, cardiovascular, respiratory, anti-ulcer, anti-inflammatory, immunosuppressive and antiepileptic drugs. Absorption may be influenced by circadian rhythms and most lipophilic drugs seem to be absorbed faster when the drug is taken in the morning compared with the evening; for water-soluble compounds, no circadian variation in the absorption of drugs has been found. Concerning drug distribution, the higher the blood flow fraction an organ receives, the higher the rate constant for transferring drugs out of the capillaries. This drug pharmacokinetic phase may be influenced by circadian variations in the protein binding of acidic and basic drugs. Drug metabolism may be influenced by daily modifications of blood flow. For drugs with a high extraction ratio, metabolism depends on hepatic blood flow, while that of drugs with a low extraction ratio depends on liver enzyme activity. Hepatic blood flow has been shown to be greatest at 8 am and metabolism seems to be reduced during the night. Finally, concerning drug elimination, the clearance of ‘flow-limited’ drugs that present a high extraction rate is affected by the blood flow delivered to the organ, independent of the cardiac output fraction supplied. Chronopharmacokinetics can explain individual differences in drug levels revealed by therapeutic drug monitoring and can be used to optimise the management of patients receiving drug therapy.

Chronopharmacokinetics of Ciclosporin and Tacrolimus

The correct use of immunosuppressive drugs has a considerable influence on the prognosis of patients with organ transplants. The appropriate utilisation of the drugs involves the administration of an adequate dosage to reach the blood concentrations that will suppress the alloimmune response, while avoiding secondary toxicities. However, transplanted patients exhibit heterogeneous immunological responses and high inter- and intraindividual pharmacokinetic variabilities. One cause of these variabilities that is rarely considered is circadian rhythms. In vitro and in vivo experiments have clearly demonstrated that all organisms are highly organised according to an internal biological clock that influences various physiological functions. Considering that the absorption, distribution, metabolism and elimination of drugs is influenced by the physiological functions of the body, it is not surprising that the pharmacokinetic, and consequently the pharmacodynamic, profiles of drugs can be influenced by circadian rhythms.Ciclosporin, a mainstay immunosuppressive drug used following organ transplantation, displays minimum blood concentration (Cmin), maximum blood concentration (Cmax) and area under the blood concentration-time curve (AUC) in the morning that are generally higher than the corresponding parameters in the evening. These observations are supported by the ciclosporin total body clearance and elimination half-life in the morning, which are, on average, higher and shorter, respectively, than those in the evening. In addition, the disposition of tacrolimus is determined by the time of administration. The tacrolimus Cmax and AUC after the morning dose are significantly higher than those after the evening dose.Finally, the results reported in this review suggest considering more carefully the chronopharmacokinetics of tacrolimus and ciclosporin in order to obtain better results with fewer adverse effects. Significantly, the morning appears to be the best time for therapeutic monitoring using the Cmin, Cmax, concentration at 2 hours after dosing and AUC to modify dosages of tacrolimus and ciclosporin. Less certain are any conclusions about whether, in order to obtain better immunosuppressive control, higher doses must be administered when these drugs are given in the evening to compensate for the higher levels of interleukin-2.

Oral gabapentin disposition in patients with epilepsy after a high-protein meal.

Summary: Purpose: To study the interaction between gaba‐pentin (GBP) and high‐protein meals, 12 patients with epilepsy were administered this drug both while in a fasting state and after a high‐protein meal.

Liposomal daunorubicin plasmatic and renal disposition in patients with acute leukemia

Abstract Liposomal formulations of anthracyclines have been developed to increase their delivery to solid tumors while reducing toxicity in normal tissues. DaunoXome (DNX, NeXstar) is a liposomal-encapsulated preparation of daunorubicin registered for treatment of Kaposis sarcoma that during prior in vitro studies showed a toxicity to leukemic cells at least comparable to that of free daunorubicin. The aim of our study was to determine DNX pharmacokinetics in 11 poor-risk patients with acute leukemia treated with DNX 60 mg/m2 IV on days 1, 3, and 5. Blood and urine samples were collected at appropriate intervals after each of the three DNX administrations. The total amount of daunorubicin (free and entrapped) (t-DNR) and of its metabolite daunorubicinol (DNRol) was assayed by HPLC. The main pharmacokinetic parameters (t1/2α 4.54 ± 0.87 h; Vdss 2.88 ± 0.93 l/m2; Cl 0.47 ± 0.26 l/h/m2) showed that in patients with acute leukemia liposomal-entrapped daunorubicin pharmacokinetics greatly differed from that observed for the conventional formulation. In fact, DNX produced mean plasma AUC levels (t-DNR AUC0–∞ 456.27 ± 182.64 μg/ml/h) about 100- to 200-fold greater than those reported for the free drug at comparable doses due to a very much lower total body clearance. Volume of distribution at steady state was 200- to 500-fold lower than for the free drug. Plasma AUC of DNRol (17.62 ± 7.13 μg/ml · h) was similar to or even greater than that observed with free daunorubicin for comparable doses. Cumulative urinary excretion showed that about 6% and 12% of the total dose of DNX administered was excreted in urine as daunorubicin and daunorubicinol, respectively. No major toxicity was encountered. Therefore, pharmacokinetic characteristics suggest that DNX may be more convenient than free daunorubicin in the treatment of acute leukemia. In fact, liposomal formulation may allow a reduction of daunorubicin captation in normal tissues, thus minimizing toxicity at least for the parent drug, and guarantee an unimpeded access to leukemic cells in the bloodstream and bone marrow, thus theoretically improving efficacy.

Calculating percentage prediction error: A user's note

The equations of calculation of percentage prediction error (percentage prediction error = [equation: see text] x 100 or percentage prediction error = [equation: see text] x 100) and similar equations have been widely used. However, not much is known about the property of this type of equation and the caution which should be taken into account when using this type of equation. Moreover, little is known about the power of percentage prediction error as statistical inference. In the present study we address these points in the use of this type of equation.

Plasma Levels of Levodopa and Its Main Metabolites in Parkinsonian Patients after Conventional and Controlled-Release Levodopa-Carbidopa Associations

The paper reports plasma levels of levodopa (LD), its main metabolites [dopamine, dihydroxyphenylacetic acid, homovanillic acid, 3-O-methyldopa (3-O-MD)] and carbidopa in 14 parkinsonian patients first treated with Sinemet and thereafter with Sinemet-CR4. A good relationship was observed between LD plasma levels and pharmacological effects. While the LD area under the curve increased after Sinemet-CR4, the same was not observed with metabolites, except with 3-O-MD. The experiments in volunteer subjects confirmed the increase in 3-O-MD in plasma after Sinemet-CR4. Higher levels were observed also in the CSF with a reduction of LD concentrations. This seems to corroborate the hypothesis of an interference with LD passage through the blood-brain barrier in humans.

Pharmacokinetic Interaction Between Everolimus and Antifungal Triazoles in a Liver Transplant Patient

Objective: TO describe the management of a pharmacokinetic interaction between azole antifungals (fluconazole and voriconazole) and everolimus in a patient who underwent an orthotopic liver transplant. Case Summary: A 65-year-old male who received an orthotopic liver transplant experienced an iatrogenic retroperitoneal duodenal perforation on postoperative day 55. His condition was subsequently complicated by severe sepsis and acute renal failure. Intravenous fluconazole 400 mg, followed by 100 mg every 24 hours according to impaired renal function, was immediately started; to avoid further nephrotoxicity, immunosuppressant therapy was switched from cyclosporine plus mycophenolate mofetil to oral everolimus 0.75 mg every 12 hours. Satisfactory steady-state minimum concentration (Cmin) of everolimus was achieved (∼5 ng/mL). On day 72 posttransplant, because of invasive aspergillosis, antifungal therapy was switched to intravenous voriconazole 400 mg every 12 hours on the first day, followed by 200 mg every 12 hours; to prevent drug toxicity, the everolimus dosage was promptly lowered to 0.25 mg every 24 hours. At that time, the everolimus Cmin averaged approximately 3 ng/mL. The concentration/dose ratio of everolimus (ie, Cmin reached at steady-state for each milligram per kilogram of drug administered) was markedly lower during fluconazole versus voriconazole cotreatment (mean ± SD, 3.49 ± 0.29 vs 11.05 ± 0.81 ng/mL per mg/kg/daily; p < 0.001). Despite intensive care, the patients condition continued to deteriorate and he died on day 84 posttransplant Discussion: Both azole antifungals were considered probable causative agents of an interaction with everolimus according to the Drug Interaction Probability Scale. The Interaction is due to the inhibition of CYP3A4–mediated everolimus clearance. Of note, prompt reduction of the everolimus dosage since the first azole coadministration, coupled with intensive therapeutic drug monitoring, represented a useful strategy to prevent drug overexposure. Conclusions: Our data suggest that during everolimus-azole cotreatment, a dose reduction of everolimus is needed to avoid overexposure. According to the different inhibitory potency of CYP3A4 activity, the reduction should be lower during fluconazole than during voriconazole cotreatment.

Cigarette smoking knowledge and perceptions among students in four Italian medical schools.

INTRODUCTION Tobacco smoking is the leading cause of premature death in the developed world. Advice and assistance by physicians help smokers quit, but little attention has been paid to the topic of tobacco dependence in the curricula of Italian medical schools. Consequently, few physicians follow the clinical practice guidelines for treating dependence. METHODS This study was conducted on 439 students at 4 Italian medical schools in 2010. Students were asked to complete a 60-item questionnaire. Two scores were computed: Score 1 assessed knowledge of the epidemiology of smoking, risks associated with smoking, and benefits of cessation. Score 2 assessed knowledge of tobacco dependence treatment guidelines and the effectiveness of treatments. A score of less than 60% indicated insufficient knowledge. RESULTS Medical students had limited knowledge of the epidemiology of smoking, attributable morbidity and mortality, and the benefits of cessation. This limited knowledge was reflected by the finding that 70% of students had a total Score 1 less than 60% of available points. Knowledge of clinical guidelines, perceived competence in counseling smokers, and treatment of addiction was also insufficient, as 76% of students achieved a total Score 2 of less than 60%. CONCLUSIONS Our data demonstrate that Italian medical students have limited knowledge about tobacco dependence, how to treat it, and the critical role of the physician in promoting cessation. Taken together with research from other countries, these findings suggest that medical schools do not offer adequate training in tobacco dependence and provide a rationale for modifying the core curriculum to include more information on tobacco dependence treatment.

Multidrug resistance modulation in vivo: the effect of cyclosporin A alone or with dexverapamil on idarubicin pharmacokinetics in acute leukemia.

AbstractObjective: To determine the effect of the coadministration of the multidrug resistance (MDR) modulators cyclosporin A (CyA) alone or plus dexverapamil (D-Ver) on idarubicin (IDA) pharmacokinetics in patients with acute leukemia. Methods: Pharmacokinetic studies were performed in 27 patients with a diagnosis of acute myelogenous leukemia (AML), who were being treated with a combination chemotherapy regimen including idarubicin and cytarabine for the induction of a first remission (n = 14), or of a second remission (n = 7), or for remission consolidation (n = 6). Of these 27 patients, nine were coadministered CyA and seven were coadministered CyA plus D-Ver as MDR modulators. Blood was sampled at appropriate intervals after each of the three IDA daily administrations. IDA and idarubicinol (IDAOL) were assayed by HPLC. Pharmacokinetic evaluations were performed by means of a two-compartment open model with zero-order absorption and first-order elimination using the WinNonlin pharmacokinetic software package. Results: CyA markedly increased the area under the concentration time-curve (AUC) of both IDA [558.26 (197.25) μg · h · l−1 vs 315.44 (158.28) μg · h · l−1; P < 0.01] and IDAOL [2896.60 (736.38) μg · h · l−1 vs 1028.49 (603.95) μg · h · l−1; P < 0.001] when coadministered as a single modulator, due to a lower total body clearance (CL) [83.51 (52.44) l · h−1 · m−2 vs 139.65 (69.45) l · h−1 · m−2; NS]. When patients received two MDR modulators simultaneously (D-Ver plus CyA), IDA exposure was essentially the same as in those of the no inhibitor group [331.29 (95.49) μg · h · l−1 vs 315.44 (158.28) μg · h · l−1; NS], whereas the IDAOL total body exposure was greater than in the no inhibitor group [2030.32 (401.11) μg · h · l−1 vs 1028.49 (603.95) μg · h · l−1; P < 0.01], even if less than in patients receiving CyA as a single MDR modulator (IDA + CyA group) [AUC 2030.32 (401.11) μg · h · l−1 vs 2896.60 (736.38) μg · h · l−1; P < 0.05], suggesting an antagonistic effect against those of CyA on IDA and IDAOL elimination and/or an unpredictable redistribution. The main pharmacokinetic parameters of IDA, such as CL and volume of distribution at steady state (Vdss), were remarkably affected by the coadministration of CyA or CyA plus D-Ver, but no statistically significant difference was noted because of IDA pharmacokinetic interpatient variation. Conclusion: The results show that CyA alone at a dose of 10 mg · kg−1 daily significantly increased systemic body exposure to both IDA and IDAOL in acute leukemia, and suggest that these pharmacokinetic effects were at least partially decreased when D-Ver was coadministered with CyA. Our findings raise important questions concerning the need for a dosage adjustment of IDA when MDR modulators are coadministered.

Blood concentrations and clinical effect of cyclosporin in psoriasis.

After approval by the Local Ethical Committee, 60 psoriatic patients, who participated in a previous pharmacokinetic study on cyclosporin A (CsA), gave their informed consent to continue to be studied during the maintenance treatment and at withdrawal. Peak concentration (Cmax), area under the concentration-time curve (AUC), bioavailability, elimination half-life, distribution volume, and body clearance were determined at monthly check-ups, along with blood pressure, psoriasis area, severity index (PASI), and creatinine serum levels. No modifications over time of treatment were observed on kinetic parameters. At the dose of 5 mg/kg in two daily administrations, a complete remission of the disease was observed after 1 months treatment. At withdrawal, a worsening of PASI appeared when CsA daily dose reached 2 mg/kg b.w., the mean trough levels or AUC values being, respectively, 100 and 2,200 ng/ml.hr. There was a trend for patients with hypertension and nephrotoxicity at the end of the maintenance treatment to have higher trough, Cmax, and AUC values. Furthermore, blood pressure and serum creatinine tended to correlate better with AUC and Cmax, than with trough levels.