Pharmacokinetic-based Dosing Individualization of Mycophenolate Mofetil in Solid Organ Transplanted Patients.

Mycophenolate mofetil (MMF) is an immunosuppressant drug approved for prophylaxis of transplant rejection in patients undergoing solid organ transplantation and is further employed in management of various autoimmune disorders. MMF exhibits notable pharmacokinetic inter- and intraindividual variability necessitating tailored therapeutic approaches to achieve optimal therapeutic outcomes while mitigating risks of adverse effects. The objective of this review was to summarize factors that influence the pharmacokinetics of MMF and its active metabolite mycophenolic acid in order to deduce recommendations for personalized treatment strategies. Presumed predictors were analysed in relation to each of the four pharmacokinetic phases, providing tools and targets for MMF dosing optimization amenable to clinical implementation.

The frequency of, and predisposing risk factors for, ciprofloxacin-induced neuro-psychiatric adverse drug reactions.

OBJECTIVES: Ciprofloxacin induces rare neuro-psychiatric adverse drug reactions (ADRs) that are, as yet, not possible to predict due to unknown predisposition factors. BACKGROUND: The aim of the analysis was to assess the frequency of neuro-psychiatric ADRs and to identify potential risk factors that predisposed patients to ciprofloxacin neurotoxicity. METHODS: This observational retrospective study involved the evaluation of the medical records of patients in the Nephrology department and 3rd Internal Clinic of the General University Hospital in Prague. RESULTS: The overall incidence of neurological ADRs was 3.6 %. No neurological ADRs developed in patients aged less than 70 years. The covariates that were significantly more prevalent in the patients who developed neuropsychiatric ADRs were as follows: higher age, a history of neuropsychiatric disorders and the use of anticonvulsants. The administration of drugs from other ATC groups, gender, weight, body mass index, body surface area, renal functions, level of C-reactive protein at the beginning of treatment and the total daily dose/kg did not differ significantly between the two groups. CONCLUSION: Ciprofloxacin neuropsychiatric ADRs are more frequent in older patients with a history of neurologic or psychiatric disorders. No other tested covariates were proven to predispose patients to neuropsychiatric ADRs during treatment with ciprofloxacin (Tab. 2, Ref. 20).

Population pharmacokinetics-pharmacodynamics of fondaparinux in dialysis-dependent chronic kidney disease patients undergoing chronic renal replacement therapy.

PURPOSE: Data on the anti-Xa efficacy of fondaparinux in dialysis-dependent chronic kidney disease (DD-CKD) patients are scarce. This study characterizes the pharmacokinetics (PK) and pharmacodynamics (PD) of fondaparinux in DD-CKD patients undergoing renal replacement therapy (RRT), to assess dosing strategies. METHODS: A retrospective, observational study was conducted using data on anti-Xa activity (112 samples) from 12 (3 male and 9 female) DD-CKD patients (median (IQR) age 71 years (63-88), weight 73 kg (59-98.5)). Eleven patients underwent high-flux or low-flux hemodialysis (HD) and one patient underwent peritoneal dialysis. Three patients were also treated with therapeutic plasma exchange (TPE). A non-linear mixed effects analysis was performed using NONMEM 7.3.0. RESULTS: The lab-specific slope of the relationship between fondaparinux concentration and anti-Xa levels was 1.18 IU/µg. In a one-compartment model, clearance (CL) and volume of distribution (Vd) were 0.05289 L/h and 5.55 L, respectively. High-flux HD was found to increase the CL of fondaparinux 2.26 times. TPE also considerably increased CL, but the fold-change could not be accurately estimated. Low-flux HD and peritoneal dialysis did not impact PK parameters. CONCLUSIONS: Model-based simulations showed that standard dosing (2.5 mg three times weekly before HD) results in a median anti-Xa activity of 0.55 IU/mL and 0.98 IU/mL, pre- and post-low-flux HD, respectively. In patients undergoing high-flux HD, these values are approximately 27% lower. Additional caution is warranted with TPE, as this treatment can reduce anti-Xa activity even further.

Dosing of Aminoglycosides in Chronic Kidney Disease and End-Stage Renal Disease Patients Treated with Intermittent Hemodialysis.

BACKGROUND: The dosing of aminoglycosides (AGs) in patients with kidney disease is challenging due to their markedly prolonged half-life, which renders pulse dosing schedules unsuitable. We performed a review of the literature that describes the pharmacokinetics of, and dosing recommendations for, AG for patients with abnormal renal functions and various renal replacement therapy modalities, focusing on patients treated with intermittent hemodialysis (iHD). SUMMARY: During one iHD session, dialysis removes a remarkable amount of the drug regardless of the dialyzer type. In patients with severely reduced kidney functions, the distribution phase is prolonged, which needs to be taken into account when drawing samples shortly after drug administration or following an iHD session. KEY MESSAGES: The doses recommended for the pulse dosing of patients without kidney disease leads to unacceptably high overall systemic exposure for patients with severely reduced kidney functions even with dosing intervals extended up to 48 h. Therefore, lower doses accompanied by extended dosing intervals must be applied for this patient group. The clinical evidence and current recommendations support the dosing of AG following, rather than before, HD sessions. In patients with end-stage kidney disease, the samples for TDM of AGs should not be drawn earlier than 2 h after end of the infusion and 4 h after the end of iHD session to allow full (re)distribution of the drug.

Adherence and blood pressure control in patients with primary aldosteronism.

PURPOSE: The aim of our study was to evaluate the adherence to mineralocorticoid receptor (MR) antagonists and other antihypertensive therapy and blood pressure control in conservatively treated patients with primary aldosteronism (PA). MATERIALS AND METHODS: Conservatively treated subjects with previously confirmed PA (n-50, 64.5 ± 9 years of age, 24% women) were investigated via our outpatient hypertension clinic. All subjects underwent regular examinations in our clinic. In addition to basic laboratory and clinical parameters, 24 h ambulatory blood pressure monitoring (ABPM) (Spacelabs) was evaluated. Unplanned blood sampling for assessment of serum antihypertensive drug concentrations by the means of liquid chromatography-mass spectrometry was performed in all patients. In case of spironolactone, its active metabolite canrenone was also evaluated. Total non-compliance was then defined as the absence of all measured antihypertensive drugs. Partial non-compliance was calculated as the absence of serum levels of at least one, but not all antihypertensive drugs prescribed. RESULTS: Good blood pressure control was detected (mean 24 h systolic/diastolic BP 130 ± 12/77 ± 9 mmHg). The average number of antihypertensive drugs was 3.9 ± 1.5. All subjects were treated by MR antagonists. 44% of patients received spironolactone (average daily dose 45 ± 20 mg) and in the remaining 56% of subjects eplerenone was administered (average daily dose 80 ± 30 mg) due to spironolactone side effects. Assessment of antihypertensive drug concentrations revealed full adherence in 80% of all subjects, partial nonadherence was noted in the remaining 20% of subjects. MR antagonist levels were detected in almost all subjects (49 out of 50). CONCLUSIONS: Good blood pressure control and adherence to therapy were detected in conservatively treated patients with PA. Eplerenone had to be used quite often as male subjects did not tolerate dose escalation due to spironolactone side effects.

Pharmacokinetic principles of dose adjustment of mTOR inhibitors in solid organ transplanted patients.

WHAT IS KNOWN AND OBJECTIVES: mTOR inhibitors possess narrow therapeutic range and substantial pharmacokinetic variability and the consequences from suboptimal dosing are serious. The aim of this review is to summarize the current knowledge about the factors influencing mTOR inhibitors pharmacokinetics and the possibility of using these relationships in order to improve its therapy individualization in solid organ transplanted patients. METHODS: Literature search from Pubmed and Web of Science databases were performed using Boolean search operators in order to identify relevant studies. RESULTS AND DISCUSSION: A total of 701 reports were identified from the initial literature search. Out of which 40 studies dealt with relationships between various factors and pharmacokinetics of mTOR inhibitors and with relevance of these associations for dosage optimization. WHAT IS NEW AND CONCLUSION: The overview of the current covariates for pharmacokinetic variability of mTOR inhibitors has been provided on the level of absorption, distribution and elimination, and consequences of these relationships for dosing optimization has been summarized.

Effective use of fondaparinux in patient with unresponsiveness to nadroparin.

WHAT IS KNOWN AND OBJECTIVE: Fondaparinux exhibits a similar mechanism of action as LMWH. Since both of these drugs bind to antithrombin and increase its affinity to factor Xa, fondaparinux is not expected to be an effective alternative anticoagulant to LMWH in case of LMWH resistance. CASE SUMMARY: We report on a case of effective anticoagulation using fondaparinux following total unresponsiveness to high doses of nadroparin administered twice daily, as confirmed via repeated anti-Xa measurements. The antithrombin levels were within the normal range. WHAT IS NEW AND CONCLUSION: To the best of our knowledge, this is the first report of the effective use of fondaparinux in the case of unresponsiveness to LMWH.

Obesity-associated changes in drug pharmacokinetics.

Pharmacokinetics of drugs in obese patients can be affected by changes in drug distribution and/or changes in elimination functions. Drug dosing based on patients weight or body surface area may not be satisfactory in terms of safety or efficacy, especially for patients with a higher degree of obesity. However, current knowledge about most drugs does not provide sufficient guidance for dose adjustment in this group of patients. This article provides an overview of factors influencing changes in pharmacokinetics of drugs in obese, including some examples (eg. analgesics, antibiotics, anticoagulants and others). Due to different changes in pharmacokinetics, which cannot always be estimated from the physical and chemical properties of drug molecular structure, it is important to assess pharmacokinetic properties of a particular drug rather than looking for general rules for the most appropriate dosing. In case of drugs with a narrow therapeutic index (aminoglycoside antibiotics and vancomycin, anticonvulsants, immunosuppressants, lithium, digoxin and theophylline), it is always advisable to measure drug plasma levels and use therapeutic drug monitoring.

Importance of vancomycin loading doses in intermittent infusion regimens.

PURPOSE: Delayed achievement of target vancomycin serum concentrations may adversely affect clinical outcomes. The objective of this retrospective study was to explore the real frequency of loading dose use and to evaluate the impact of loading dose for the achievement of vancomycin PK/PD target in adult patients treated with intermittent vancomycin. As a secondary aim we determined optimal vancomycin loading dose based on individual pharmacokinetic calculations. METHODS: Vancomycin pharmacokinetic models were computed using two-compartmental analysis. Based on these models AUC24 were calculated. Unpaired t-test was used to compare AUC24 achieved in patients treated with and without vancomycin loading dose. RESULTS: Vancomycin loading dose was administered only in 17.8% patients. Volume of distribution and clearance median values (interquartile range) for vancomycin in whole study population (n = 45) were 0.69 (0.55-0.87) L/kg and 0.0304 (0.0217-0.0501) L/h/kg, respectively. The AUC24 was significantly higher in patients taking loading dose compared with the group without loading dose: mean (SD) AUC24 was 496 (101) vs. 341 (77) mg h/L. Proportion of patients reaching PK/PD goal was 87.5% and 24.3% with and without loading dose administration, respectively. Considering individual pharmacokinetic parameters optimal vancomycin loading dose was 27.5 mg/kg of body weight. CONCLUSIONS: Loading dose administration plays crucial part in rapid attainment of vancomycin PK/PD target in adult patient treated with intermittent vancomycin, although it is not frequently used in clinical practise. The optimal loading dose of 25-30 mg/kg of body weight should be routinely administered to adult patients treated with intermittent vancomycin.

Role of Dipyrone in the High On-Treatment Platelet Reactivity amongst Acetylsalicylic Acid-Treated Patients Undergoing Peripheral Artery Revascularisation.

OBJECTIVE: To evaluate the effects of dipyrone on sensitivity to aspirin (acetylsalicylic acid [ASA]) in patients who underwent peripheral artery vascular reconstruction. SUBJECTS AND METHODS: Impedance aggregometry and light transmission aggregometry were used to determine the effects of dipyrone on ASA treatment in 21 patients. Blood samples were drawn in a 7-day period after the surgery. The cut-off value for high on-treatment platelet reactivity (HTPR) was set at < 65% of aggregation inhibition for impedance aggregometry. For light transmission aggregometry the cut-off value for arachidonic acid-induced aggregation was set at > 20% of aggregating platelets, and the cut-off value for epinephrine-induced aggregation was > 44% of aggregating platelets. The cut-off value for each method was derived from a large number of patients treated with a daily dose of 100 mg of ASA. RESULTS: We found HTPR in 14 (67%) of the 21 patients. None had primary resistance to ASA, i.e., after the addition of ASA in vitro all samples showed antiplatelet efficacy. Regression analysis showed a possible correlation between lower efficacy of ASA treatment and higher daily doses of dipyrone (p = 0.005 for impedance aggregometry, p = 0.04 for light transmission aggregometry), higher platelet count (p = 0.005 for impedance aggregometry), and shorter time from surgery (p = 0.03 for impedance aggregometry). CONCLUSION: HTPR occurs in 67% of ASA-treated patients after lower limb vascular surgery. The occurrence of HTPR correlates with the daily dose of dipyrone. Therefore, dipyrone should not be used as a postoperative analgesic in ASA-treated patients after peripheral artery revascularisation due to its influence on the effectiveness of ASA.

Meropenem-induced Valproic Acid Elimination: A Case Report of Clinically Relevant Drug Interaction.

We present two case reports of drug interaction between valproic acid and meropenem. In comparison with expected population-kinetic based serum levels, we observed 90.8 and 93.5% decrease in valproic acid serum levels during concomitant administration with meropenem. If carbapenems need to be administered to valproic acid treated patient, other anticonvulsant addition seems to be the appropriate as most probably the valproic acid dose escalation would not be sufficient to achieve therapeutic serum concentration.

5-fluorouracil Toxicity Mechanism Determination in Human Keratinocytes: in vitro Study on HaCaT Cell Line.

5-fluorouracil (5-FU) and capecitabine therapy is often accompanied by palmar-plantar erythrodysesthesia (PPE) which is manifestation of 5-FU toxicity in keratinocytes. The main mechanisms of 5-FU action are thymidylate synthase (TS) inhibition which can be abrogated by thymidine and strengthened by calciumfolinate (CF) and incorporation of fluorouridinetriphosphate into RNA which can be abrogated by uridine. For proper PPE treatment 5-FU mechanism of action in keratinocytes needs to be elucidated. We used the 5-FU toxicity modulators uridine, thymidine and CF to discover the mechanism of 5-FU action in human keratinocyte cell line HaCaT. To measure the cellular viability, we used MTT test and RTCA test. CF did not augment 5-FU toxicity and 5-FU toxicity was weakened by uridine. Therefore, the primary mechanism of 5-FU toxicity in keratinocytes is 5-FU incorporation into RNA. The uridine protective effect cannot fully develop in the presence of CF. Thymidine addition to 5-FU and uridine treated cells not only prevents the toxicity-augmenting CF effect but it also prolongs the 5-FU treated cells survival in comparison to uridine only. Therefore, it can be assumed that in the presence of uridine the 5-FU toxicity mechanism is switched from RNA incorporation to TS inhibition. Although particular 5-FU toxicity mechanisms were previously described in various cell types, this is the first time when various combinations of pyrimidine nucleosides and CF were used for 5-FU toxicity mechanism elucidation in human keratinocytes. We suggest that for PPE treatment ointment containing uridine and thymidine should be further clinically tested.

Pharmacotherapy of carbamazepine-treated patient after bariatric surgery: a complex interplay between altered absorption and drug-drug interactions.

Changes in absorption and bioavailability of drugs have been described after bariatric surgery, especially shortly after the procedure. When a significant drug-drug interaction also occurs, it is difficult to predict the final combined effect of the surgery and the interaction. In this article, we present a case report of a patient with chronic psychiatric poly-medication including carbamazepine, a strong cytochrome P450 3A4 (CYP3A4) inducer. Significant changes in serum drug concentrations were observed during the 6 months after the surgery, including increased levels of quetiapine and trazodone, that cannot be attributed to the post-surgical alteration of absorption from the gastrointestinal tract. The influence of fluctuating carbamazepine levels on concomitant medication seemed to outweigh the effect of reduced absorption after surgery. This report highlights the need for careful pre-surgical evaluation of the patient's pharmacotherapy and pre- and post-operative therapeutic drug monitoring to prevent destabilisation of chronic conditions.

Bioavailability of Orally Administered Drugs After Bariatric Surgery.

PURPOSE OF REVIEW: Oral drug absorption after bariatric surgery is likely to be altered, but the impact of different bariatric surgery procedures on individual drugs is not uniform. The aim of this article is to describe factors influencing the bioavailability of orally administered drugs after bariatric surgery and to provide readers with practical recommendations for drug dosing. We also discuss the medications that may be harmful after bariatric surgery. RECENT FINDINGS: The fundamental factors for enteral drug absorption are the production of gastric acid; the preserved length of the intestine, i.e., the size of the absorption surface and/or the preserved enterohepatic circulation; and the length of common loop where food and drugs are mixed with digestive enzymes and bile acids. Bypassing of metabolizing enzymes or efflux pumps and changes in intestinal motility can also play an important role. Significant changes of drug absorption early after the anatomic alteration may also be gradually ameliorated due to gradual intestinal adaptation. The most affected drugs are those with low or variable bioavailability and those undergoing enterohepatic circulation. Attention should also be paid to oral drug formulations, especially in the early postoperative period, when immediate-release and liquid formulations are preferred. The changes in oral bioavailability are especially clinically meaningful in patients treated with drugs possessing narrow therapeutic index (e.g., oral anticoagulants, levothyroxine, and anticonvulsants) or in acute conditions (e.g., anti-infectives); nevertheless, it may also influence the therapeutic value of chronic therapy (e.g., antidepressants. antihypertensives, antiplatelets, statins, PPIs, contraceptives, and analgesics); therapeutic effect of chronic therapy is further influenced by pharmacokinetic alterations resulting from weight loss. Therapeutic drug monitoring, periodical clinical evaluation, and adequate dose adjustments are necessary. Due to safety reasons, patients should avoid oral bisphosphonates, regular use of non-steroidal anti-inflammatory drugs, and, if possible, corticosteroids after bariatric surgery.

Vancomycin loading dose individualization in a population of obese patients undergoing haemodialysis based on population pharmacokinetic model.

This study aimed to develop a vancomycin population pharmacokinetic model in obese adult patients treated with intermittent haemodialysis and propose a model-based loading dose strategy ensuring attainment of newly recommended AUC-based PK/PD target. Retrospective cross-sectional analysis was performed among obese haemodialysis dependent adult patients treated with intravenous vancomycin. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were used to identify the optimal loading dose for PK/PD target attainment during the first 48 h of treatment. Therapeutic drug monitoring data from 27 patients with a BMI of 30.2-52.9 kg/m2 were analysed. Among all tested variables, only LBM as a covariate of vancomycin Vd significantly improved the model, while vancomycin CL did not correlate with any of the tested variables. The median (IQR) value from the conditional mean of individual estimates of Vd and CL was 68.4 (56.6-84.2) L and 0.86 (0.79-0.90) L/h, respectively. To ensure optimal vancomycin exposure during the first 48 h of therapy, the vancomycin loading dose of 1500, 1750, 2000, 2250, 2500 and 2750 mg should be administered to obese patients with a lean body mass of ˂50, 50-60, 60-70, 70-80, 80-85 and >85 kg, respectively.

A novel dosing approach for rituximab in glomerular diseases based on a population pharmacokinetic analysis.

OBJECTIVES: Rituximab is being increasingly prescribed for the treatment of autoimmune glomerular diseases. While it is highly effective for some diseases, the response is less predictable for others, which may be due to differing requirements in terms of the dosing according to the disease type and variations concerning exposure to the drug. METHODS: We compiled novel rituximab dosing schedules according to pharmacokinetic analysis of data gathered from rituximab treated patients in a tertiary referral nephrology centre between May 2020 and June 2023. The population-pharmacokinetic analysis was based on the rituximab dosing, the patients' characteristics, rituximab levels and anti-rituximab antibodies. RESULTS: The analysis, which was based on data from 185 patients, clearly highlighted differing rituximab dosing requirements for patients with ANCA associated vasculitis and minimal change disease compared to those with membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This corresponded to the good treatment response of the first two diseases and the unreliable efficacy for the others. The model predicts the rituximab pharmacokinetics with high degree of accuracy when body weight, proteinuria, type of glomerulonephritis, treatment length and anti-rituximab antibodies formation are used as covariates. We proposed a dosing schedule with shortened dosing intervals for difficult-to-treat diagnoses with high proteinuria. CONCLUSION: In order to ensure reliable and comparable exposure of rituximab with respect to the full range of glomerular diseases, the dosing schedule should be adjusted for membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This is largely, but not solely, due to the enhanced level of unselective proteinuria in these diseases.

Elimination and penetration of amikacin into urine in patients with decreased glomerular filtration rate.

Background: Amikacin monotherapy is recommended for urinary tract infection (UTI) treatment with multi-resistant pathogens. Even though amikacin efficacy in the treatment of UTIs is dependent on its urinary concentration, there are no robust data proving that sufficiently high urinary concentration is reached in patients with reduced glomerular filtration rate (GFR). Methods: A prospective study to monitor amikacin penetration into urine of 70 patients [40 males, median (interquartile range) age 70 (65-79) years] with different levels of glomerular filtration decline, including patients treated by dialysis, was conducted. The bactericidal efficacy of amikacin in urine samples has been evaluated. Results: Patients with estimated GFR (eGFR) <30 mL/min had significantly lower median amikacin urinary concentration than patients with eGFR >30 mL/min (89.75 vs 186.0 mg/L, P < .0001; 200.5 vs 830.0 mg/L, P < .0001; and 126.0 vs 408.0 mg/L, P < .0001 for minimal, maximal and minimal together with maximal concentrations, respectively). The amount of amikacin eliminated in the first 10-13 h after dose administration was dependent on eGFR (r2 = 0.6144, P < .0001). The urinary concentration of amikacin in patients treated by dialysis was indirectly proportional to pH of urine. The plasma concentrations of amikacin did not correlate with urinary levels in patients in either of the GFR categories. Microbiological evaluation showed that the critical urinary concentration for efficacy of amikacin during UTI monotherapy in patients treated by dialysis is 100 mg/L. We found that 4 out of 11 patients treated by dialysis did not reach this level during the treatment. Conclusion: Systemic administration of amikacin monotherapy in patients treated by dialysis is questionable as the concentrations of amikacin in their urine are often below the threshold of effectivity. Amikacin plasma concentrations are not a major determinant of amikacin concentration in urine, therefore pulse dosing is neither necessary nor safe in patients treated by dialysis, and may cause undesirable toxicity.

Expanding options of supportive care in IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with a potentially serious prognosis. At present, management of IgAN is primarily based on therapeutic lifestyle changes, and excellent blood pressure control and maximized supportive treatment with the combination of inhibition of the renin-angiotensin-aldosterone system with either inhibitors of angiotensin-converting enzyme or angiotensin II receptor blockers and inhibitors of sodium-glucose cotransporter-2, and possibly in the future also with endothelin antagonists. Supportive care currently represents the cornerstone of treatment of IgAN. Targeted-release formulation of budesonide should replace systemic corticosteroids in patients with higher proteinuria and active histological lesions. New treatment options are aimed at immunopathogenesis of IgAN including depletion or modulation of Galactose-deficient-Immunoglobulin A1-producing B cells, plasma cells, and the alternate and/or lectin pathway of complement. The exact place of monoclonal antibodies and complement inhibitors will need to be determined. This article reviews potential supportive therapies currently available for patients with IgAN.