Franz Maximilian Rasche

Pharmacokinetics and Pharmacodynamics of Systemically Administered Glucocorticoids

Glucocorticoids have pleiotropic effects that are used to treat diverse diseases such as asthma, rheumatoid arthritis, systemic lupus erythematosus and acute kidney transplant rejection. The most commonly used systemic glucocorticoids are hydrocortisone, prednisolone, methylprednisolone and dexamethasone. These glucocorticoids have good oral bioavailability and are eliminated mainly by hepatic metabolism and renal excretion of the metabolites. Plasma concentrations follow a biexponential pattern. Two-compartment models are used after intravenous administration, but one-compartment models are sufficient after oral administration.The effects of glucocorticoids are mediated by genomic and possibly nongenomic mechanisms. Genomic mechanisms include activation of the cytosolic glucocorticoid receptor that leads to activation or repression of protein synthesis, including cytokines, chemokines, inflammatory enzymes and adhesion molecules. Thus, inflammation and immune response mechanisms may be modified. Nongenomic mechanisms might play an additional role in glucocorticoid pulse therapy.Clinical efficacy depends on glucocorticoid pharmacokinetics and pharmacodynamics. Pharmacokinetic parameters such as the elimination half-life, and pharmacodynamic parameters such as the concentration producing the half-maximal effect, determine the duration and intensity of glucocorticoid effects. The special contribution of either of these can be distinguished with pharmacokinetic/pharmacodynamic analysis. We performed simulations with a pharmacokinetic/pharmacodynamic model using T helper cell counts and endogenous Cortisol as biomarkers for the effects of methylprednisolone. These simulations suggest that the clinical efficacy of low-dose glucocorticoid regimens might be increased with twice-daily glucocorticoid administration.

Pharmacokinetics of valganciclovir and ganciclovir in renal impairment

Valganciclovir is the oral prodrug of ganciclovir. The pharmacokinetics of valganciclovir in patients with renal impairment is not known. Furthermore, it is not known whether there are any pharmacokinetic differences between patients who are positive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) and healthy subjects.

Thrombocytopenia and Acute Renal Failure in Puumala Hantavirus Infections

Low platelet counts are a novel predictive marker suitable for risk-adapted patient management.

Cyclophosphamide Pulse Therapy in Advanced Progressive IgA Nephropathy

For advanced progressive primary IgA nephropathy (IgAN) no established therapy exists. We conducted a prospective, uncontrolled trial to evaluate the effect of intravenous cyclophosphamide pulse (CyP) therapy on the course of advanced progressive IgAN. Twenty-one patients (mean age 52 ± 10 years; male/female 20/1) with biopsy-proven IgAN without crescentic extracapillary proliferation and a serum creatinine of more than 2.0 mg/dl and/or an increase more than 25% in the previous 3 months were included. Patients were treated with CyP (750 mg/m2 body surface area) every 4 weeks for 6 months and low dose oral prednisolone. The loss of renal function per year was significantly reduced from 16% before therapy to 4% after therapy (p < 0.001). A further increase >25% of serum creatinine after therapy was observed in 8 patients after 0.7 years (range 0.3–3.0 years), and 3 of these patients developed end-stage renal disease. Proteinuria decreased significantly during CyP therapy. A low nadir of white blood cell and platelet count was associated with a better renal outcome (p = 0.025). In conclusion, CyP therapy and low dose oral prednisolone is effective in preserving renal function in a subgroup of patients with advanced progressive IgAN.

Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid After Enteric‐Coated Mycophenolate Versus Mycophenolate Mofetil in Patients With Progressive IgA Nephritis

Mycophenolic acid can be administered orally using mycophenolate mofetil or enteric‐coated mycophenolate. In renal transplant patients on immunosuppressant combination therapy the overall mycophenolic acid exposure after oral dosing with mycophenolate mofetil and enteric‐coated mycophenolate is similar. This study compared pharmacokinetics and pharmacodynamics of mycophenolic acid after equivalent doses of enteric‐coated mycophenolate (360 mg twice daily) or mycophenolate mofetil (500 mg twice daily) in 7 patients with progressive IgA nephritis (glomerular filtration rate 20–35 mL/min) using a randomized crossover design. The pharmacokinetics of mycophenolic acid concentrations and pharmacodynamics (using inosine 5′‐monophosphate dehydrogenase activity as a bio‐marker) were sequentially monitored for 12 hours. After enteric‐coated mycophenolate treatment, the mycophenolic acid peak concentration (Cmax = 12.8 vs 6.0 μg/mL, P < .05) and the overall exposure were significantly higher (AUC = 60.9 vs 40.7 μgh/mL, P < .05), and the apparent clearance was significantly lower (CL/F = 7.9 vs 10.7 L/h, P < .05) as compared to that after mycophenolate mofetil. Paradoxically, inosine 5′‐monophosphate dehydrogenase activity was not significantly different. In conclusion, the steady‐state mycophenolic acid exposure was higher during treatment with enteric‐coated mycophenolate as compared to mycophenolate mofetil, which might be explained by more extensive enterohepatic recycling of mycophenolic acid after administration of enteric‐coated mycophenolate, whereas inosine 5′‐monophosphate dehydrogenase suppression was not different.

High‐dose intravenous immunoglobulin pulse therapy in patients with progressive immunoglobulin A nephropathy: a long‐term follow‐up

In progressive immunoglobulin A nephropathy (IgAN), intravenous immunoglobulin (IVIg) treatment has been used to delay disease progression, but the long‐term efficacy is largely unknown. We report the clinical outcomes after IVIg therapy in six male patients with progressive IgAN [median glomerular filtration rate (GFR) 31 ml/min per 1·73 m2] followed for a median observation period of 8 years. In this single‐arm, non‐randomized study, IVIg was given monthly at a dose of 2 g/kg body weight for 6 months. The course of renal function was assessed by linear regression analysis of GFR and proteinuria, and was compared to eight patients with IgAN (median GFR 29 ml/min per 1·73 m2) without IVIg as a contemporaneous control group. IgAN disease progression was delayed after IVIg therapy on average for 3 years. The mean loss of renal function decreased from − 1·05 ml/min per month to − 0·15 ml/min per month (P = 0·024) and proteinuria decreased from 2·4 g/l to 1·0 g/l (P = 0·015). The primary end‐point (GFR < 10 ml/min or relapse) occurred 5·2 years (median; range 0·4–8·8) after the first IVIg pulse, and after 1·3 years (median; range 0·8–2·4) in the control group (P = 0·043). In Kaplan–Meier analysis, the median renal survival time with IVIg was prolonged by 3·5 years (IVIg 4·7 years versus control 1·2 years; P = 0·006). IVIg pulse therapy may be considered as a treatment option to reduce the loss of renal function and improve proteinuria in patients with progressive IgAN.

Irinotecan in Cancer Patients with End-Stage Renal Failure

Objective: To observe and report on the pharmacokinetics of irinotecan in a patient with end-stage renal failure (ESRF) who was undergoing hemodialysis. Case Summary: A 64-year-old man with metastatic colorectal cancer who was on hemodialysis was treated with Irinotecan 50 mg/m2 weekly for 3 weeks, followed by 1 week with no treatment. As the drug was well tolerated, the dosage was increased to 80 mg/m2 after 2 cycles. Diagnostic testing of a hepatic lesion after 2 and 6 treatment cycles showed stable disease. The carcinoembryonic antigen value decreased to 40% of its pretreatment level. Pharmacokinetically, our patient had a lower apparent clearance and a higher maximum concentration of the active metabolite SN-38 (130 L/h/m2, maximum concentration 0.4 μg/L per mg of irinotecan) compared with published values from patients with normal renal function. Removal of irinotecan and its metabolites by hemodialysis was negligible. Discussion: The reason for the unexpectedly low clearance of SN-38 in our patient remains unclear. We speculate that inhibition of the OATP1B1 transporter by uremic toxins could be an explanation. Such a mechanism would explain excessive irinotecan toxicity, as reported in previous case reports of patients undergoing hemodialysis. Conclusions: We conclude that approximately two-thirds of the standard weekly irinotecan dosage regimen should be considered in patients with ESRF.

Single daily dose of cyclosporine in patients with primary glomerulonephritis and nephrotic syndrome

AIMS Single daily dose cyclosporine (SDD-CsA) might be a new option providing comparable efficacy, increased compliance and less nephrotoxicity compared to standard twice-daily dose cyclosporine (TDD-CsA). The aim of this trial was to prove the feasibility of SDD-CsA as primary and secondary maintenance therapy in patients with nephrotic syndrome. METHODS We treated 25 adult patients with nephrotic syndrome and chronic primary glomerulonephropathy with SDD-CsA for a period of 12 months or more. 12 patients were pre-treated with twice-daily dose cyclosporine (TDD-CsA) and were then switched secondarily to a single daily dose after a median period of 8 months (sSDD-CsA). 13 patients were treated primarily with single daily dose cyclosporine (pSDD-CsA). RESULTS In primary SDD-CsA patients, proteinuria decreased significantly from 9.2 - 0.8 g/l (p = 0.02) and serum protein increased significantly from 54 - 71 g/l (p = 0.03) during the study period. In secondary SDD-CsA patients, serum protein increased further (64 - 69, p = 0.04) after switching to SDD-CsA. In secondary SDD-CsA patients, the median total daily CsA dose was significantly lower (200 mg) with SDD-CsA compared to previous twice-daily dosing (300 mg, p = 0.01). Serum creatinine did not differ significantly before and after therapy and between the groups. CONCLUSIONS SDD-CsA is effective in patients with nephrotic syndrome as primary and secondary maintenance therapy. SDD-CsA allows for significantly lower total daily doses, probably with less nephrotoxicity.

Digenic Inheritance of Hepatocyte Nuclear Factor-1α and -1β With Maturity-Onset Diabetes of the Young, Polycystic Thyroid, and Urogenital Malformations

H eterozygous mutations of the POU A/homeodomain transcription factors hepatocyte nuclear factor (HNF)-1 and -1 cause maturity-onset diabetes of the young (MODY) in humans (1). HNF-1 and -1 act in a complex network of transcription factors regulating tissue-specific gene expression in the pancreas and other epithelial organs. Patients with mutations of HNF-1 (MODY5) are characterized by urogenital malformations, while extrapancreatic manifestations in patients with diabetes and HNF-1 mutations (MODY3) are not well known (2).

New AUC-Based Method to Estimate Drug Fraction Removed by Hemodialysis

Background: A supplemental dose is often necessary after hemodialysis depending on the amount of drug removed by hemodialysis. However, there are different methods of estimating this amount, and most methods ignore drug rebound after hemodialysis. In this report we present a new area under the concentration curve (AUC)-based method that provides an estimate of the drug fraction removed by hemodialysis including drug rebound. Methods: Valganciclovir, the oral prodrug of ganciclovir, was administered to 6 patients with end-stage renal disease. Hemodialysis was performed after 32 h. The fraction of ganciclovir removed by hemodialysis was estimated using the new AUC-based method, a classical method (using the slope on and off hemodialysis), the back-extrapolation method, and a reference model (a two-compartment model with zero-order input and first-order elimination). Results: The AUC-based method and the back-extrapolation method provided accurate estimates of the fraction of ganciclovir removed by hemodialysis (47 ± 6 and 46 ± 5%, respectively) compared to the reference model (49 ± 3%). The classical method, which does not account for the rebound of ganciclovir concentrations after hemodialysis, overestimated the removed fraction by 9% (58 ± 3%). Conclusions: The new AUC-based method and the back-extrapolation method accurately estimate the drug fraction removed by hemodialysis for drugs with a rebound after hemodialysis. The AUC-based method is more robust and as efficient compared to the back-extrapolation method.