Time of effect duration and administration interval for sitagliptin in patients with kidney failure.

A measure correlating the time course of the effect with the time course of concentrations could be helpful in drug dosing. We propose a new equation with explicit solutions for calculating the effect duration. A specific effect fraction is selected (fr) and the time of fractional effect duration (TED.fr) can be derived as a function of the elimination half-life by combining linear elimination kinetics with sigmoid effect dynamics. This new measure is applied to the example of sitagliptin, whose elimination half-life increases from 10.1 to 28.4 h in patients with kidney failure. Under normal multiple-dose conditions, the 24-h sitagliptin administration interval corresponds to a 0.90 time of fractional effect duration (TED.90). A dose reduction to one-fourth or 25 mg every 24 h is proposed for patients with kidney failure; this results in a TED.90 of 45 h, i.e. 21 h longer than the proposed 24-h administration interval (+88 %). The proportional dosing alternative of 100 mg every 96 h would result in a TED.90 of 64 h, which is 32 h less than the 96-h administration interval (-33 %). With a half dose of 50 mg and a doubled administration interval of 48 h, the TED.90 is 51 h in kidney failure, only 3 h longer than the latter administration interval (+6 %). We conclude that our general equation can be applied to rapidly calculate the specific time of effect duration for the different dose schedules.

Development of a sensitive phospho-p70 S6 kinase ELISA to quantify mTOR proliferation signal inhibition.

BACKGROUND: Drug blood levels can only serve as a surrogate because of the lack of information on the drug's direct pharmacological effects in the individual patient. Measurement of the mammalian target of rapamycin (mTOR) activity dependent on the phosphorylation status of p70 S6 kinase (p70 S6K) offers a practical way for monitoring pharmacodynamic drug activity, with the potential to better assess the state of immunosuppression in individual patients. MATERIAL AND METHODS: Here, we established a novel in vitro model system by treating Jurkat cells and peripheral blood mononuclear cells with different concentrations of sirolimus after stimulation with phorbol 12-myristate 13-acetate. RESULTS: A dose-dependent reduction of the p70 S6K phosphorylation status was demonstrated by Western blot and a newly established enzyme-linked immunosorbent assay (ELISA). Relative phospho-p70 S6K values from ELISA and relative densities from Western blot analysis in peripheral blood mononuclear cells revealed a strong correlation (Spearman correlation coefficient r s = 0.7, P = 0.01). Finally, parallel assays confirmed a sirolimus dose-dependent reduction of cytokine production and cell proliferation in the in vitro model. CONCLUSIONS: Pharmacodynamic monitoring of mTOR inhibition with a p70 S6K ELISA could guide mTOR inhibitor immunosuppression therapy toward a more individualized therapy. The usage of this technique now has to be evaluated in a clinical series of patients.

Biomarkers as a tool for management of immunosuppression in transplant patients.

Therapeutic drug monitoring is a well-established approach in transplantation medicine to guide immunosuppressive therapy. However, it cannot always predict the effects of immunosuppressive drugs on immune cells, because it does not reflect any aspect of an individual patient's immune system. Pharmacodynamic monitoring is a more recent strategy to provide information about the biologic effect of a specific drug or drug combination on the individual transplant patient. Currently, there is a large number of different biomarkers that either directly (specific markers) or indirectly (global markers) relate to the pharmacodynamic effects of immunosuppressive drugs and are under investigation as potential candidates to be introduced in clinical practice. Such biomarkers may be useful to identify patients at risk of developing acute rejection, infection, or cancer as well as patients who are suitable for minimization of immunosuppressant therapy and may be helpful to manage the timing and rate of immunosuppressant weaning. Serial longitudinal monitoring may allow maintenance of an individualized immunosuppressive regimen. Thus, biomarker monitoring is a potential complementary tool to therapeutic drug monitoring. This review summarizes the current state of knowledge about the use of a number of global or drug-specific pharmacodynamic biomarkers. It is not a comprehensive overview of the literature available, but rather an evidence-based reflection by experts who are intensively involved in scientific work in this field.

Explicit solution of integrated 1 - exp equation for predicting accumulation and decline of concentrations for drugs obeying nonlinear saturation kinetics.

To describe nonlinear, saturable pharmacokinetics, the Michaelis-Menten equation is frequently used. However, the Michaelis-Menten equation has no integrated solution for concentrations but only for the time factor. Application of the Lambert W function was proposed recently to obtain an integrated solution of the Michaelis-Menten equation. As an alternative to the Michaelis-Menten equation, a 1 - exp equation has been used to describe saturable kinetics, with the advantage that the integrated 1 - exp equation has an explicit solution for concentrations. We used the integrated 1 - exp equation to predict the accumulation kinetics and the nonlinear concentration decline for a proposed fictive drug. In agreement with the recently proposed method, we found that for the integrated 1 - exp equation no steady state is obtained if the maximum rate of change in concentrations (Vmax) within interval (Tau) is less than the difference between peak and trough concentrations (Vmax x Tau < C peak - C trough).

N-terminal pro-brain natriuretic peptide and renal insufficiency as predictors of mortality in pulmonary hypertension.

BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-proBNP) is a byproduct of the brain natriuretic peptide (BNP) that was shown to be of prognostic value in pulmonary hypertension (PH). The role of NT-proBNP in PH has to be determined, especially under the influence of renal impairment that might lead to an accumulation of the peptide, and may be a sign of increased mortality per se. METHODS: We assessed NT-proBNP, BNP, renal function, and hemodynamic parameters (during right-heart catheterization) in 118 consecutive patients with isolated PH, excluding left-heart disease. Depending on the calculated creatinine clearance, patients were classified into different groups of renal function. Correlation analysis was performed on all key parameters. Results were then compared between the levels of renal function. The prognostic value of each parameter was assessed during a mean follow-up period of 10 months. RESULTS: Twenty-two patients (approximately 19%) had significantly impaired renal function (creatinine clearance < 60 mL/min). Although the overall levels of NT-proBNP were correlated with hemodynamics, we observed no correlation in the group with significant renal dysfunction. Moreover, NT-proBNP was related to creatinine clearance. Finally, NT-proBNP and renal insufficiency were independent predictors of death during univariate and multivariate analysis, whereas BNP only predicted mortality in univariate analysis. CONCLUSIONS: The diagnostic accuracy of NT-proBNP as a parameter of the hemodynamic status is diminished by renal function. However, NT-proBNP could be superior to BNP as a survival parameter in PH because it integrates hemodynamic impairment and renal insufficiency, which serves as a sign of increased mortality per se.

Malacoplakia in a renal transplant recipient.

Malacoplakia is a rare, inflammatory condition characterized histologically by distinct histiocytes with pathognomonic inclusion calcospherules called Michaelis-Gutmann bodies. It most often affects the urinary tract of immunocompromised patients. We describe a case of renal allograft parenchymal malacoplakia in a transplant recipient. Moreover, we report the imaging and histological findings and review the literature of this rare disorder.

Performance of a phosphoflow assay to determine phosphorylation of S6 ribosomal protein as a pharmacodynamic read out for mTOR inhibition.

OBJECTIVES: The S6 ribosomal protein (S6RP) is phosphorylated by the mammalian target of rapamycin (mTOR). The objective of this study was to assess the analytical suitability of a commercial kit-based phosphoflow cytometry protocol using whole blood (WBS) to measure the level of phosphorylated S6RP (p-S6RP) in T-cell subsets to study the pharmacodynamic effects of mTOR inhibitors (mTORi). DESIGN AND METHODS: A kit was used for fixation and permeabilization of mitogen-stimulated cells, and p-S6RP was assessed separately in CD3+CD4+ and CD3+CD8+ cells by employing an anti-phospho-Ser235/236 antibody. Specificity, linearity, within-run precision and stability were investigated in either WBS spiked with everolimus and non-mTORi immunosuppressants or in WBS from patients on immunosuppressive therapy (n=56). In addition, healthy controls (n=10) and patients without immunosuppression (n=10) were included. A comparison (n=15) with an established western blot method based on anti-phospho p70S6 kinase (Thr389) was made by splitting WBS. RESULTS: Everolimus decreased p-S6RP in vitro concentration dependently (0.00-27.4µg/L). This effect was also confirmed in vivo after a single dose of everolimus to healthy volunteers (n=3). However, spiking WBS with 500µg/L cyclosporine also decreased p-S6RP. The within-run coefficient of variation was <18% in transplant patients and <27% in healthy controls for both cell subsets. Sample stability for p-S6RP analysis was limited (<24h). p-S6RP was significantly decreased in CD3+CD8+ cells of patients treated with sirolimus (p=0.02) but not with everolimus. No significant correlation between the phosphoflow- and western blot method was noted. CONCLUSION: The phosphoflow assay of p-S6RP performed well analytically, but sample stability, specificity, and method comparison results question its fitness for clinical purposes.

Safety and efficacy of everolimus after kidney and hematopoietic stem cell transplantation.

BACKGROUND: The aim of this retrospective study was to investigate the efficacy of everolimus at our institution and to report incidence and type of side effects in patients who underwent kidney transplantation or hematopoietic stem cell transplantation (HSCT). MATERIAL/METHODS: Electronic medical records were evaluated for 122 patients (76 men and 46 women) treated with everolimus between January 2000 and January 2009. Of these patients, 81 had undergone kidney transplantation (mean age: 56±12 years) and 41 patients were treated with HSCT (mean age: 47±11 years). RESULTS: Everolimus was discontinued in a total of 53% of patients (n=64) with no difference observed in kidney transplant recipients vs. stem cell transplanted patients (p=0.85). In one half of the patients, cessation of the drug was due to a lack of long-term efficacy (n=32). In the other half, everolimus was discontinued due to side effects (n=32). However, patients with side effects had no elevated everolimus concentrations (5.5±2.3 vs. 5.2±1.7 ng/ml; p=0.39). Pneumonitis (n=5) or proteinuria over 1.5 g per day (n=13) were only observed in kidney transplant patients, while polyomavirus-induced cystitis (n=3) and thrombotic thrombocytopenic purpura (n=7) were only observed in stem cell transplanted patients. CONCLUSIONS: Everolimus was an effective immunosuppressive agent in half of the patients. A quarter of all patients developed side effects resulting in discontinuation of the drug. The profile of side effects in kidney recipients clearly differs from hematopoietic stem cell transplanted patients.

Minimal access kidney transplant: a novel technique to reduce surgical tissue trauma.

OBJECTIVES: Minimally invasive surgery and minimal access surgery has replaced conventional surgical procedures during the last 15 years with benefits including a decrease in postoperative pain, time spent convalescing, early return to normal activities, and pleasing cosmetic results. Many centers perform kidney transplant through an oblique or J-shaped approach deep into the iliac fossa. Both approaches have possible disadvantages regarding the extent of tissue trauma. Therefore, we introduced a new minimal access kidney transplant technique in our kidney transplant program in 2008 and report the outcomes of the first 10 patients transplanted with this technique. MATERIALS AND METHODS: Between November 2008 to May 2009, ten kidney recipients were subjected to the minimal access kidney transplant technique. These patients represent a consecutive series of kidney transplants performed by the senior surgeon or under the supervision of the senior surgeon of transplant surgery. RESULTS: The mean (± SD) age of the recipients was 47 ± 14.7 years (range, 28-67 y), the body mass index was 25 ± 2.02 (range, 23-30), the time of procedure was 126.2 ± 27.5 minutes (range, 90-165 min) with a mean (± SD) anastomoses time of 27.7 ± 8.4 minutes (range, 19-45 min). Follow-up for all recipients was at least 18 months. There was no reintervention necessary, no wound infections, no primary nonfunction or a delayed graft function, no need for dialysis, no acute rejection episodes, no graft loss, no wound dehiscence, no incisional hernia, or lymphocele. Furthermore, no urologic complications or vascular complications were observed. CONCLUSIONS: Our reported technique was used on heart-beating donor kidneys as well as on living-donor organs and is safe with less comorbidity. This minimal access kidney transplant technique might be an alternative procedure for avoiding some of the disadvantages of conventional approaches used for kidney transplant.

Drug therapy in patients with chronic renal failure.

BACKGROUND: Roughly 20% of patients in hospital have impaired kidney function. This is frequently overlooked because of the creatinine-blind range in which early stages of renal failure are often hidden. Chronic kidney disease is divided into 5 stages (CKD 1 to 5). METHODS: Selective literature search. RESULTS: Methotrexate, enoxaparin and metformin are examples of drugs that should no longer be prescribed if the glomerular filtration rate (GFR) is 60 mL/min or less. With antidiabetic (e.g. glibenclamide), cardiovascular (e.g. atenolol) or anticonvulsive (e.g. gabapentin) drugs, the advice is to use alternative preparations such as gliquidone, metoprolol or carbamazepine which are independent of kidney function. Drug dose adjustment should be considered with antimicrobial (e.g. ampicillin, cefazolin), antiviral (e.g. aciclovir, oseltamivir) and, most recently, also for half of all chemotherapeutic and cytotoxic drugs in patients with impaired kidney function (with e.g. cisplatin, for instance, but not with paclitaxel). CONCLUSION: Decisions concerning drug dose adjustment must be based on the pharmacokinetics but this is an adequate prerequisite only in conjunction with the pharmacodynamics. There are two different dose adjustment rules: proportional dose reduction according to Luzius Dettli, and the half dosage rule according to Calvin Kunin. The latter leads to higher trough concentrations but is probably more efficient for anti-infective therapy.

[Questionnaire surveying nephrologists on drug dose adjustment in patients with impaired kidney function]. / Umfrage zur Arzneimitteldosierung bei Niereninsuffizienz unter nephrologisch tätigen Arzten.

OBJECTIVE: Our intention was to assess knowledge and requirements related to drug dose adjustment in patients with impaired kidney function. METHOD: In 2005, we sent a questionnaire containing 22 questions to nephrologists in Germany and Austria. With 77 responses, the study was not representative. However, it was probably of importance for the target group of practising physicians and potential users of a future drug information system. RESULTS: Only 28% of the responding colleagues use the package inserts; these are obviously not considered to be an obligatory guideline for dose adjustment. The most common dosing problems (p < 0.05) were associated with anti-infective (48%) and anti-cancer drugs (25%). The greatest problems with dosing were encountered within intensive care units (29%). The risk of excessive dosing is estimated significantly more serious than the risk of underdosing (51% vs. 23%, p = 0.02). There was support for the statement that for cephalosporin antibiotics the trough levels are more important than peak levels (58% vs. 27%, p < 0.01). However, only 8% knew that in patients with impaired kidney function, trough concentrations of aminoglycosides and vancomycin need to be higher than in patients with normal kidney function for adequate peak levels to be obtained. Forty-five percent of respondents erroneously presumed that ceftriaxone must be adjusted to the kidney function. Half of the respondents were incorrect in assuming that ceftriaxone or moxifloxacin would be removed by dialysis. CONCLUSIONS: We see the need for more knowledge-based information on drug dosing in patients with kidney impairment and those in the intensive care unit. The risk to life posed by underdosage might be underestimated, especially for anti-infective drugs.

Review on pharmacokinetics and pharmacodynamics and the aging kidney.

In people who are aged >65 years, pharmacokinetics are influenced more by the loss of kidney function than by the aging process of any other organ. A GFR of 30 to 60 ml/min, suggestive of stage 3 kidney disease, is observed in 15 to 30% of elderly people. Drug dosing must be adjusted to both changing pharmacokinetics and pharmacodynamics; the pharmacodynamics might be influenced by the aging of other organs, too. Using our NEPharm database, we extracted abstracts with pharmacokinetic parameters since 1999 from a weekly PubMed search. The recorded data were analyzed and compared with published recommendations on drug dosage and use in the elderly. Purely age-related changes in pharmacokinetic parameters were recorded from publications on 127 drugs. The analysis of our NEPharm records revealed an average (mean +/- SD) age-related prolongation of half-life of 1.39-fold (corresponding to +39 +/- 61%). Contrasting to common opinion, mean changes in clearance (-1 +/- 54%) and volume of distribution (+24 +/- 56%) were even less. The modest changes in pharmacokinetics do not suggest general dosage modifications in the elderly for most drugs. Changes in pharmacodynamics justify the common medication rule in the elderly-"start low + go slow"-especially for drugs that act on the central nervous system; however, in the case of anti-infective and anticancer therapy, the rule should be "hit hard = start high + go fast" to produce the target effect also in the elderly.

Mean residence time as estimated from cropped and truncated moments.

UNLABELLED: For non-compartmental concentration-time curve analysis the mean residence time (MRT) is usually estimated using numerical summation and log-linear extrapolation. However, when the initial ear of the curve is cropped and the terminal tail is truncated the MRT can be estimated without extrapolation using numerical methods alone. This paper is to evaluate the error of the cut MRT derived from cropped and truncated moments. The cut MRT is estimated from exclusively measured but non extrapolated concentrations. Mono-exponential kinetics after single intravenous dosing is considered. Two conditions define the acceptable cutoff error of 5% or less: For cropping, the first concentration must be measured immediately after dosing at time t1 that is 0.14 times the elimination half-life (t1 = 0.14 x T1/2). For truncation, the concentration must be observed for a near 2 log decline period (tn) or, exactly, 6.51 times the elimination half-life (tn = 6.51 x T1/2). From data of previous studies, the MRT truncation error of only 0.39% for methylprednisolone (CAS 2375-3-3) was estimated with an observation period of 10 times one half-life (24 h = 10.4 x 2.3 h) but 4.3% for cyclosporin (CAS 59865-13-3), with an investigation interval of only 2 times one half-life (12 h = 2 x 6.1 h). For the complex kinetics of raloxifene (CAS 82640-04-8) it was seen that the cropping and truncation errors are non additive. CONCLUSION: If a reliable extrapolation is impossible, the cut MRT can be estimated only from measured concentrations. However, the cropping and the truncation maneuvers should be considered simultaneously to counterbalance the cutoff errors.

Biochemical monitoring of mTOR inhibitor-based immunosuppression following kidney transplantation: a novel approach for tailored immunosuppressive therapy.

BACKGROUND: Immunosuppressive therapy with the mammalian target of rapamycin (mTOR) inhibitors requires a fine balance between allograft maintenance and drug-related side effects. METHODS: In this study we examined the feasibility of monitoring TOR inhibitor-based immunosuppression by assessment of the phosphorylation status at the Thr(389) site of the p70S6 kinase in peripheral blood mononuclear cells (PBMCs). At total of 36 patients with renal transplants and 8 healthy controls were enrolled. RESULTS: We found that sirolimus treatment was associated with a pronounced inhibition of p70S6 kinase phosphorylation, as compared to healthy donors or otherwise immunosuppressed patients. In sirolimus-treated patients, phosphorylation of the p70S6 kinase was significantly inhibited when sirolimus trough levels were > 6 ng/mL. In contrast, for trough levels <6 ng/mL, the degree of inhibition of p70S6 kinase phosphorylation showed a high degree of interindividual variability. We recorded a total of five clinical relevant rejection episodes in this patient category. Intriguingly, rejecters uniformly maintained a high degree of phosphorylation independent of the sirolimus trough level whereas non-rejecters showed a significant inhibition of phosphorylation. CONCLUSION: Therefore, the phosphorylation status of the p70S6 kinase appears to provide more relevant information on the desired effect of sirolimus in target cells as compared to trough level measurements. Moreover, this assay provides an opportunity to safely titer down sirolimus levels to avoid overimmunosuppression and, on the other hand, to identify patients with insufficient TOR inhibitor therapy that are at risk for rejection.