Published online Nov 28, 2020. doi: 10.5500/wjt.v10.i11.356
Peer-review started: May 15, 2020
First decision: May 24, 2020
Revised: June 18, 2020
Accepted: September 18, 2020
Article in press: September 18, 2020
Published online: November 28, 2020
Transplant clinics in developing countries continually aim to provide successful renal transplant care at the lowest possible cost, and have reported that the combined use of ketoconazole with low-dose tacrolimus increases tacrolimus bioavailability through metabolic inhibition via P450 3A4.
This combination has been used successfully in adult transplant patients, but has not been demonstrated in pediatric patients. In order to expand successful renal transplant care to children and adolescents at the lowest possible cost, our pediatric renal transplant clinic uses a post-transplant tacrolimus-sparing strategy via inhibition of CYP3A4.
The objective of this study was to identify the changes in tacrolimus dose and plasma concentration associated with the use of ketoconazole as a pharmacokinetic booster. We describe the safety, efficacy and the associated cost reduction of this combination from a retrospective cohort of children with a kidney transplant in the FUNDANIER.
We carried out a retrospective observational study, with a pre-post single arm design collecting information from 2011 to 2015 from a cohort of patient records stored in FUNDANIER database before and after the addition of ketoconazole to the usual immunosuppressive protocol. Inclusion criteria for chart review were: Age younger than 18 years, at least 3 mo post-transplantation, currently on the tacrolimus protocol, and switched to ketoconazole/tacrolimus combination during their outpatient transplant clinic attendance. Charts were reviewed to identify the point at which ketoconazole was added to the post-transplant treatment. A total of six documented visits were reviewed for each patient chart during the study: 3 visits prior to ketoconazole initiation and 3 visits after the combination was initiated. An average of 2 mo between each visit was documented.
Of the 25 patient charts reviewed, 12 (48%) patients were male and the average age of the patients was 13 years. Twenty-four (96%) transplants were from living donors. There was a non-significant difference between the mean tacrolimus doses six months and two months prior to ketoconazole: -0.10 ± 0.04 (95%CI: 0.007, -0.029), P = 0.23. However, the difference between the mean tacrolimus doses six months prior to ketoconazole initiation and six months after ketoconazole addition was significant: 0.06 ± 0.05 (95%CI: -0.034, -0.086) P < 0.001. All tacrolimus doses were reduced by 45% after the addition of ketoconazole. Therapeutic levels of tacrolimus were preserved during the study period and patients demonstrated an improvement in eGFR. The combination of tacrolimus and ketoconazole resulted in a 21% reduction in cost.
Patients experienced an effective dose-reduction of tacrolimus with the administration of ketoconazole. No relevant variations in tacrolimus serum levels, number of rejections, or significant liver toxicity were observed. This allowed for a safe, efficacious, and significant cost reduction in pediatric immunosuppressive therapy.
In the FUNDANIER clinic population, the safety and efficacy of tacrolimus and ketoconazole were successfully observed in pediatric post-renal transplant patients demonstrating a significant cost reduction. However, larger studies need to be carried out to capture broad safety and efficacy profiles in this patient population. These types of interventions are of added benefit in the low to middle income countries setting where access to medications post-transplant is problematic.