Retrospective Cohort Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Transplant. Nov 28, 2020; 10(11): 356-364
Published online Nov 28, 2020. doi: 10.5500/wjt.v10.i11.356
Exploring the safety and efficacy of adding ketoconazole to tacrolimus in pediatric renal transplant immunosuppression
Sindy Méndez, Brooke M Ramay, Angie Aguilar-González, Randall Lou-Meda
Sindy Méndez, Angie Aguilar-González, Randall Lou-Meda, Fundación para el Niño Enfermo Renal - FUNDANIER, Hospital Roosevelt Guatemala, Guatemala 01010, Guatemala
Brooke M Ramay, Department of Pharmaceutical Chemistry, Universidad del Valle de Guatemala, Guatemala 01015, Guatemala
Author contributions: Méndez S, Ramay BM, Aguilar-González A and Lou-Meda R conceptualized and designed the study, acquired, analyzed and interpreted data, supported drafting the article and making critical revisions; all the authors have given final approval of the version of the article to be published.
Institutional review board statement: The Research Ethics Committee from the Faculty of Humanities and Science, at the Universidad del Valle de Guatemala reviewed and approved the study protocol and all study documents (QF-010-febrero2015).
Informed consent statement: Researchers did not collect any personal identifiers to carry out this retrospective chart review. Informed consent was waived and approved by the ethics committee.
Conflict-of-interest statement: The authors have no conflicts of interest to report.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Brooke M Ramay, BSc, PharmD, Pharmacist, Professor, Department of Pharmaceutical Chemistry, Universidad del Valle de Guatemala, 18 Avenida 11-95, Guatemala 01015, Guatemala. bramay@uvg.edu.gt
Received: May 15, 2020
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
Processing time: 191 Days and 21.2 Hours
ARTICLE HIGHLIGHTS
Research background

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.

Research motivation

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.

Research objectives

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.

Research methods

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.

Research results

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.

Research conclusions

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.

Research perspectives

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.