Pharmacokinetic Drug Interaction of Mycophenolate With Co-Amoxiclav in Renal Transplant Patients

Abstract

Mycophenolate mofetil (MMF) is used in renal transplantation. Given orally, it is rapidly hydrolyzed to the active moiety, mycophenolic acid (MPA) (1). MPA is metabolized in the liver excreted in the bile as pharmacologically inactive MPA 7-O-glucuronide. MPA 7-O-glucuronide is converted back to MPA by β-glucuronidase enzyme (2). This enzyme is produced by gram- negative bacteria, which are part of the normal human intestinal flora. MPA is then reabsorbed (enterohepatic recycling), which accounts for between 10% and 60% of the total dose-interval MPA area under the curve (AUC) (1). Concentration-controlled MPA dosing by therapeutic drug monitoring of MPA reduces rejection episodes in renal allograft recipients. The target MPA-AUC0–12 hr is 30 to 60 mg · h/L (3). We routinely follow a concentration-controlled MPA dosing for our renal allograft recipients. In the Clinical Pharmacology Unit of our institution, MPA-AUC is measured from 10 sampling time points over 6 hr, and a validated extrapolation equation is applied to predict the full 12-hr interdose AUC (MPA-AUC0–12corr) (4). Renal allograft recipients, especially in developing countries, are at increased risk of infections of urinary tract, respiratory tract, and other infections requiring treatment with antibiotics. We present an interaction between MPA in two patients treated with Amoxicillin-Clavulanate (co-amoxiclav). CASE 1 A 37-year-old male renal allograft recipient was prescribed prednisolone, tacrolimus, and MMF (2250 mg/day) after renal transplantation. Within a week after transplantation, the MPA-AUC0–12corr was 21.6 mg hr/L. The total MMF dose was increased to 4000 mg/day, and the repeat AUC measurement after 5 days was 72.5 mg hr/L. The dose of MMF was reduced to 3250 mg/day, and the AUC, repeated almost 3 months after transplantation, was 122.9 mg hr/L. The MMF dose was further reduced to 2000 mg/day, and the MPA-AUC0–12corr measured at two subsequent visits over the following 3 months was 48.7 and 48.1 mg · h/L. Three months later, he was prescribed co-amoxiclav elsewhere for lower respiratory tract infection. One week after initiation of co-amoxiclav, the measured MPA-AUC0–12corr decreased by 39% to 28.9 mg · h/L. During this period, the serum creatinine, serum albumin, hemoglobin, and liver function tests were normal, and no other drug changes were made. Although a repeat MPA-AUC measurement after discontinuation of co-amoxiclav could not be performed, this decrease in MPA-AUC raised the possibility of an interaction between MPA and co-amoxiclav. CASE 2 A 14-year-old boy (second renal transplant) was prescribed prednisolone, tacrolimus, and MMF from the time of transplantation. He presented to this hospital 6 weeks posttransplant and was prescribed MMF 500 mg three times per day, and MPA-AUC was measured over the full 8-hr period. The MPA-AUC0–8 hr was 20.9 mg · h/L. His MMF dose was increased to 2250 mg/day (as two divided doses). MPA-AUC0–12corr measured 10 days later was 64.4 mg · h/L. The dose of MMF was reduced to 2000 mg/day, but MPA-AUC was not determined. At that time, he developed urinary tract infection for which he was prescribed co-amoxiclav. Ten days later, the measured MPA-AUC0–12corr was 24.0 mg · h/L. The other laboratory investigations were normal, and no other drug changes were made throughout this period. Co-amoxiclav was withdrawn, and MPA-AUC0–12corr measured after 5 days on the same dose of MMF was 45.9 mg · h/L. This represents a 91% increase in the MPA-AUC0–12corr just 5 days after withdrawal of co-amoxiclav (Fig. 1).FIGURE 1.: Changes in mycophenolic acid (MPA) concentration time profile with and without Co-amoxiclav.DISCUSSION In both the patients, there was a significant reduction in MPA-AUC when co-amoxiclav was coadministered with mycophenolate. In case 2, there was then a significant increase in the MPA-AUC 5 days after withdrawal of co-amoxiclav. Borrows et al. reported a median reduction of 46% in MPA trough concentration when measured within 3 days of initiation of amoxicillin and ciprofloxacin. After a 14-day course, they reported a median recovery of 79% 2 weeks after discontinuing the antibiotics (5). Naderer et al. (6) also suggested that concomitant treatment of MMF with antibiotics such as norfloxacin and metronidazole in healthy subjects resulted in a reduction in the MPA-AUC and that this could be due to a decrease in enterohepatic recycling. The mechanism of this interaction could be co-amoxiclav's action on intestinal flora affecting the deglucuronidation and enterohepatic recycling of MPA. This finding assumes importance as lower MPA-AUC increases the risk of rejection episodes in renal transplant patients. It highlights the need for caution when renal transplant patients on mycophenolate are treated with antibiotics, especially in the early posttransplant period. A rapid alteration in MMF dose during the standard 10- to 14-day course of antibiotic may not be necessary. However, in high-risk patients, in those on low-dose calcineurin inhibitors, or calcineurin inhibitor or steroid sparing regimen, and in those requiring prolonged use of antibiotics, therapeutic drug monitoring and dose adjustment of MPA would be advisable. Prabha Ratna1 Binu S. Mathew1 Vellaichamy M. Annapandian2 Kuppusamy Saravanakumar1 Gopal Basu2 Veerasamy Tamilarasi2 Denise H. Fleming1 1 Clinical Pharmacology Unit, Department of Pharmacology & Clinical Pharmacology, Christian Medical College, Vellore, Tamil Nadu, India 2 Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India