Coadministration of fluconazole to boost subtherapeutic sirolimus concentrations: A case report

Camilo Scherkl; Andreas D Meid; Sven E Cuntz; Laura Classen; Johanna Weiss; David Czock; Walter E Haefeli

doi:10.1002/prp2.1198

. 2024 Apr 18;12(3):e1198. doi: 10.1002/prp2.1198

Coadministration of fluconazole to boost subtherapeutic sirolimus concentrations: A case report

Camilo Scherkl ¹, Andreas D Meid ¹, Sven E Cuntz ², Laura Classen ², Johanna Weiss ¹, David Czock ¹, Walter E Haefeli ^1,^✉

PMCID: PMC11025614 PMID: 38635290

Abstract

Individual sirolimus whole blood concentrations are highly variable, critically influenced by the concomitant use of cytochrome P450 (CYP) 3A inducers or inhibitors, and also modulated by food. Therapeutic drug monitoring is therefore recommended, especially at treatment start or in circumstances that can influence sirolimus exposure. In this case report, we highlight the challenge of achieving therapeutic sirolimus concentrations and present pragmatic solutions with regimen adaptions, pharmacokinetic enhancement (use of a drug–drug interaction), concentration monitoring, and subsequent modeling of population pharmacokinetics to support treatment decisions. In a 69‐year‐old female patient with allogeneic hematopoietic stem cell transplantation, sirolimus concentrations were stable until she developed cerebral toxoplasmosis with tonic–clonic seizures. During treatment of this acute infection, sirolimus concentrations dropped to subtherapeutic levels and remained largely unaffected by dose increases. [Correction added on 4 May 2024, after first online publication: The word “tacrolimus concentrations” has been changed to “sirolimus concentrations” in the preceding sentence.] Only the simultaneous administration of the CYP3A4 inhibitor fluconazole and a shortening of the sirolimus dosing intervals to a (non‐approved) twice‐daily administration led to successful control of the concentrations, which ultimately even made a dose reduction possible. This intervention resulted in an increase of sirolimus mean trough concentration to 5.85 ng/mL, i.e., into the desired target range. Additionally, a higher ratio of sirolimus trough levels/daily dose from 26.9 to 109 ng/mL/mg/kg/day was achieved with the initiation of fluconazole. Thus, this case report describes the use of clinical pharmacological concepts and pharmacokinetic modeling to optimize treatment strategies in an individual patient. This strategy could be generalized to other CYP inhibitors and other treatment regimens.

Keywords: cytochrome P‐450 enzyme inhibitors, fluconazole, pharmacokinetics, sirolimus

During a toxoplasmosis infection in a patient with hematopoietic stem cell transplantation, sirolimus concentrations fell into the subtherapeutic range and therapeutic concentrations could not be achieved despite dose escalation. This was finally achieved by CYP3A4 inhibition with fluconazole (pharmacoenhancement) and twice‐daily (off‐label) administration of sirolimus.

graphic file with name PRP2-12-e1198-g001.jpg

Abbreviations

C/D: Concentration dose ratio
CL₁: Clearance from central compartment
CL₂: Clearance between central and peripheral compartments
C _min: Trough concentration
CYP: Cytochrome P450
DDI: Drug–drug interaction
K _m: The drug amount at 50% of the maximum absorption rate
P‐gp: P‐glycoprotein
PopPK: Population pharmacokinetics
TDM: Therapeutic drug monitoring
V ₁: Volume of distribution of central compartment
V ₂: Volume of distribution of peripheral compartment
V _m: Maximum absorption rate

1. INTRODUCTION

Sirolimus is an immunosuppressant that is primarily metabolized by cytochrome P450 (CYP) 3A isozymes and transported by the efflux transporter P‐glycoprotein (P‐gp). Consequently, coadministration of CYP3A/P‐gp inducers or inhibitors can impact sirolimus exposure by affecting both its bioavailability and elimination. Additionally, inter‐patient and intra‐patient variability in sirolimus clearance is large when ciclosporin and prednisone are coadministered, which is evident by a 4.5‐fold variation in apparent oral clearance between patients. ¹ Routine therapeutic drug monitoring (TDM) is therefore recommended, especially when it is uncertain whether target therapeutic concentrations have been achieved, e.g., when dosing regimens are changed or comorbidities or potentially modulating comedications are present. In these cases, trough concentration (C _min) monitoring in whole blood is a pragmatic approach. Because of the long half‐life of sirolimus (62 h), adequate sirolimus exposure should be confirmed 5–7 days after commencing treatment or after a dosage change. ¹ The target range for C _min of sirolimus in patients following hematological stem cell transplantation ranges between 3 and 14 ng/mL. ²

TDM with sparse data can be assisted by population pharmacokinetic (PopPK) modeling to explain observations, predict pharmacokinetics under new (e.g., new regimen and other comedication) even non‐steady‐state conditions, and ultimately provide a model‐based decision support for dose adjustment in the individual patient. ³ In this case report, we highlight the challenge of achieving therapeutic sirolimus concentrations and present pragmatic solutions that include adjustment of the therapeutic regimen, pharmacokinetic enhancement (i.e., intentional use of a drug–drug interaction, DDI), concentration monitoring, and PopPK modeling to support a dosing regimen that rapidly leads to a C _min in the desired target range.

2. CASE REPORT

A 69‐year old White woman weighing 66 kg with a history of allogenic hematopoietic stem cell transplantation (pretreated with rituximab, then with sirolimus, eltrombopag, and a comedication of esomeprazole and ursodeoxycholic acid), iron overload (deferasirox), arterial hypertension (amlodipine, bisoprolol, candesartan, and clonidine), prophylaxis for cytomegalovirus (valganciclovir), prophylaxis for veno‐occlusive disease (pravastatin), and a previous reactivation of Epstein–Barr virus was admitted to the neurology department due to cerebral toxoplasmosis (newly treated with pyrimethamine, sulfadiazine, and folic acid), tonic–clonic seizures (levetiracetam, single 2.5 mg dose of midazolam), fever of unknown origin (history of pneumonia) (ceftazidime), and dysphagia. Liposomal intravenous amphotericin B was additionally administered to prevent fungal infections during immunosuppression. To ensure adequate food and drug intake, she was fed via nasogastric tube and later percutaneous endoscopic gastrostomy. On laboratory examination, leukocytes, platelets, erythrocytes, hemoglobin, and hematocrit were slightly below the normal range, γ‐glutamyl transpeptidase and C‐reactive protein were elevated 3.5 and 6 times above normal, respectively, and serum electrolytes, renal function, alkaline phosphatase, aspartate aminotransferase, urea, total bilirubin, and albumin levels were normal.

Before the current episode, sirolimus C _min in whole blood ranged between 2.2 and 9.7 ng/mL, with most values exceeding 3.3 ng/mL using doses between 1 and 3 mg/day. The mean concentration/dose (C/D) ratio, calculated as whole blood concentration in ng/mL divided by the total daily dose in mg/kg body weight, was 189 ± 23.4. No therapeutic sirolimus exposure was achieved after admission and initiation of treatment for epileptic seizures and toxoplasmosis (Figure 1). Initially, she received 5 mg/day of sirolimus (5 mL of Rapamune® 1 mg/mL solution via nasogastric tube, always between the administration of nutrition), which was increased to 9 mg daily because of persistent C _min values <4 ng/mL. However, after 1 week of treatment with 9 mg/day (assumed steady‐state), the sirolimus C _min values were still considered subtherapeutic (2.9–4.2 ng/mL) and C/D ratios were extremely low (25.7 ± 1.36), suggesting low sirolimus absorption, high systemic drug clearance, or both.

Sirolimus concentration/dose (C/D) ratio over time before (blank circle) and during fluconazole (400 mg/day; filled circle) in a female patient with subtherapeutic sirolimus concentrations. The C/D ratio is calculated as sirolimus C _min (ng/mL)/sirolimus daily dose (mg/kg/day). One measurement (day −3, indicated by a square) is not considered in the C/D ratio calculations as it was not a C _min value.

3. INTERVENTION

To distinguish between poor bioavailability and increased elimination, we determined the sirolimus pharmacokinetics during the elimination phase (on day 24 after admission to the neurological ward, 3 days before fluconazole initiation) by drawing blood samples 2 h (expected peak concentration), 12 h, and 24 h (C _min) after sirolimus administration. This enabled the use of PopPK modeling to determine individual pharmacokinetic parameters, indicating an accelerated elimination of sirolimus. No obvious reasons for an accelerated metabolism were found as the patient was a carrier of CYP3A5*3/*3 (rs776746 = non‐expressor) and had received only sporadic doses of known inducers of CYP3A (metamizole ⁴ ) during her stay (a total of 11 g in 21 days).

In view of these findings, a change in the sirolimus regimen to twice‐daily administration with coadministration of a CYP3A inhibitor was planned. Considering the patient's comorbidities, two options seemed promising, that is, either replacing amlodipine with diltiazem for arterial hypertension or amphotericin B with fluconazole for prophylaxis of fungal infections. ⁵ , ⁶ Diltiazem was rejected and the treating physicians decided to administer fluconazole instead of amphotericin B. At that time, the mean sirolimus C _min was 3.5 ng/mL under a maintenance dose of 9 mg sirolimus/day. With a daily sirolimus dose of 9 mg and concomitant oral fluconazole 400 mg once daily, sirolimus C _min increased to 4.7 ng/mL on day 3 after initiation. The sirolimus regimen was then changed to 4.5 mg twice daily, which further increased C _min to 8.2 ng/mL, and allowed to reduce the daily dose to 6 mg (3 mg twice daily) and then to 4 mg (2 mg twice daily) with corresponding stable sirolimus concentrations of 5.85 ± 0.49 ng/mL over the following days (1–4 days after dose change) (Figure 1). Afterward, the sirolimus concentrations remained in the desired range (3.1–9.5 ng/mL) for more than 4 weeks.

The mean C/D ratio of sirolimus from the 2‐week period before fluconazole (daily doses 5–9 mg) increased from 26.9 (±1.36) to 109 (±5.13) as calculated from the values after the third day of the intervention (Figure 1). Thus, concomitant use of fluconazole resulted in a 4.05‐fold increase in the C/D ratio and more than halved the maintenance dose required to maintain the desired target C _min of sirolimus.

To further support this treatment change and explain sirolimus pharmacokinetic variability, we applied a PopPK model developed by Wu and coworkers ⁷ to estimate individual pharmacokinetic parameters a posteriori by means of Bayesian inference (Figure 2). ⁸

Two‐compartment model with a saturable Michaelis–Menten absorption kinetic. CL₁ Clearance from central compartment; CL₂ Clearance between central and peripheral compartments; K _m the drug amount at 50% of the maximum absorption rate; V _m maximum absorption rate.

Parameter estimation from the initial situation without fluconazole (sirolimus 5 mg/day) revealed a significantly increased apparent oral sirolimus clearance of 30.7 L/h compared to the population mean of 12.9 L/h estimated by Wu and coworkers ⁷ (Figure 3A). After pharmacokinetic enhancement with fluconazole, the individual apparent oral clearance decreased to 14.1 L/h, which is close to the population‐typical value (Figure 3B, Table 1).

Model‐based pharmacokinetic simulations of different treatment regimens. The dashed line indicates the target concentration in this patient of 5 ng/mL. (A) Sirolimus concentration‐time profile of the patient during once daily sirolimus administration before fluconazole. Closed circles represent the measured sirolimus concentration with an overlay of the model‐predicted concentration‐time profile. Between hours 192 and 216, sirolimus pharmacokinetics was determined. (B) Once‐daily sirolimus administration after initiation of fluconazole with switch to twice‐daily administration after 48 h. (C) Estimated effect of fluconazole on sirolimus concentration‐time profiles after once‐daily (1, 2, 3, and 4 mg) and twice‐daily (0.5, 1, 1.5, and 2 mg) administration of sirolimus (D).

TABLE 1.

Individual estimates of the pharmacokinetic parameters of sirolimus ^a ^, ^b .

Treatment conditions	CL₁ (L/h)	V ₁ (L)	CL₂ (L/h)	V ₂ (L)
Sirolimus before fluconazole	30.7	33.7	253	305
Sirolimus during fluconazole	14.1	81.3	8.56	361

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Abbreviations: CL₁: Clearance from central compartment; CL₂: Clearance between central and peripheral compartments; V ₁: Volume of distribution of central compartment; V ₂: Volume of distribution of peripheral compartment.

^{^a}

The model of Wu and coworkers ⁷ was used in a Bayesian approach to estimate the best individual value for a PK parameter from its posterior distribution. This posterior information was obtained by combining an existing model (prior information) with (sparse) data.

^{^b}

We excluded the covariate hematocrit, but kept the fixed effects of the maximum absorption rate (V _m) and the drug amount at 50% of the maximum absorption rate (K _m) (V _m = 13.8 μg/L*h, K _m = 4.56 mg) and allowed for inter‐individual variability in the parameters CL₁, CL₂, V ₁, and V ₂ to obtain the individual pharmacokinetic parameters.

Simulations with the individual parameters determined by the model showed that without fluconazole enhancement, the desired target concentration of 5 ng/mL was difficult to achieve with once‐daily administration even at higher doses (Figure 3C left). In contrast, significantly reduced maintenance doses divided into two administrations successfully reached the desired range (Figure 3C,D).

4. DISCUSSION

We cared for a patient with prolonged subtherapeutic sirolimus exposure despite increasing her daily doses from 1 to 9 mg/day over weeks. With a C/D ratio of 25.7 at the highest sirolimus dose of 9 mg daily, the C/D ratio in our patient was extremely low compared to corresponding values reported in transplant recipients (150–380 ⁹ ). Although we ultimately did not find a clear cause for this patient's apparently accelerated metabolism and increased dose requirements, we did find a way to manage it sustainably and safely.

Profound changes in C/D ratios may be caused by changes in bioavailability, systemic drug clearance, or both. Considering the apparent clearance, which was 2.4 times higher than estimated by Wu et al., ⁷ our findings suggest that systemic sirolimus clearance was substantially increased. The increment could not be explained by a genetic contribution of CYP3A5 since this patient was a non‐expressor. Furthermore, a normal C/D ratio in this patient 6 weeks earlier (mean C/D ratio 189) suggests an acute effect on sirolimus pharmacokinetics. Metamizole was identified as an inducer of CYP3A but does not appear to explain the findings due to the sporadic administration of metamizole, as the patient only received a cumulative dose of 11 g spread over 21 days, although some contribution from CYP3A induction cannot be entirely ruled out. A substantial induction of CYP3A4 is reported for high metamizole doses of 3 g/day over 3 or more consecutive days ⁴ and lower doses appear to cause less induction. ¹⁰ In addition, a single case report describes a decrease in ciclosporin concentration with sulfadiazine therapy for toxoplasmosis. ¹¹ This decrease could be attributed to the effect on CYP3A4, as ciclosporin is also a CYP3A4 substrate. To date, no evidence of similar effects with sirolimus has been reported. As discontinuation and rechallenge of sulfadiazine was not recommended or clinically indicated in our patient, we could not verify whether sulfadiazine contributed to the decrease in sirolimus concentrations in our patient.

To the best of our knowledge, this case report describes the first deliberate attempt to raise sirolimus exposure with a CYP3A4 inhibitor. Various choices for CYP3A inhibition were available, which were also appropriate for managing the patient's comorbidities. The substitution of fluconazole for amphotericin B allowed a CYP3A4 inhibitor to be introduced seamlessly without compromising the prophylactic antifungal effect. By intentionally using a DDI (pharmacokinetic enhancement) and modifying the dosing regimen to twice‐daily administration, we successfully inhibited sirolimus degradation, presumably leading to increased bioavailability and/or reduced systemic clearance (4.05‐fold higher C/D ratio) and increased sirolimus C _min to the target range, resulting in stable therapeutic exposure and also small drug cost savings of 10 €/day. As expected for a victim compound with a relatively long half‐life and similar to a previously described patient case, ⁵ the effect of fluconazole on sirolimus exposure slowly evolved over several days (Figure 1).

Optimally dosed sirolimus therapy faces challenges due to pharmacokinetic variability between and within patients. Therefore, personalized sirolimus therapy relies on C _min measurements but C _min‐guided TDM alone can be challenging because the target C _min is sometimes difficult to achieve. ¹² Our patient case demonstrates the value of combining clinical pharmacological strategies with modeling in individual cases to support an off‐label change in dosing interval to twice‐daily administration, to which there seemed to be no alternative. After several unsuccessful initial dose adjustments, we were able to achieve stable therapeutic sirolimus concentrations in this patient.

Concurrently, fluconazole may also have influenced other coadministered CYP substrates and therefore a comprehensive medication review and monitoring is necessary. A single dose of 2.5 mg midazolam was administered i.v. shortly after starting fluconazole. Fluconazole increases the AUC of oral midazolam by 270% and C _max by 130%, which can increase sedative effects. ¹³ , ¹⁴ In our patient, this interaction was probably insignificant, as only a low single dose was chosen and this was administered intravenously, that is, via a route of administration with a significantly lower interaction. ¹⁴ In addition, fluconazole likely also decreases the clearance of amlodipine and can increase amlodipine's hypotensive effects. ¹⁵

Pharmacokinetic boosting is a common practice in HIV treatment, where cobicistat or ritonavir are used as boosting agents. This strategy is not limited to this indication, as it has been employed in the past to reduce the cost of expensive therapies. ¹⁶ Currently, pharmacokinetic boosting is used to decrease therapy costs and increase the bioavailability of, for example, kinase inhibitors ¹⁷ , ¹⁸ and other cytostatic drugs. ¹⁹ In this patient's case the moderate CYP inhibitor fluconazole was administered instead of the more commonly used strong inhibitors such as ritonavir, cobicistat, ketoconazole, itraconazole, or clarithromycin. Physicians using this strategy should be aware of potential interactions with co‐medications, such as opioids, anticoagulants, antiarrhythmics, and anxiolytics. ²⁰ These interactions can be managed, as demonstrated in the boosting regimes for patients living with HIV and other comorbidities. The management involves dose adjustments, closer monitoring for side effects, or switching to drugs with no or less interaction with the boosting perpetrator drug.

These findings are limited by the fact that sirolimus C _min values were in steady state before the intervention while a true sirolimus steady state was likely not reached thereafter. Additionally, several single doses of metamizole were administered after the intervention, which can increase sirolimus elimination through CYP3A4 induction when administered repeatedly. ⁴ This and possibly also sulfadiazine ¹¹ may have contributed to the fluctuating C/D ratios with higher standard deviations after the intervention. Furthermore, effects of fluconazole on sirolimus bioavailability and systemic clearance could not be separated, which would have required intravenous administration, which is not approved in Germany.

5. CONCLUSION

In a single patient with persisting subtherapeutic sirolimus exposures, appropriate exposure was ultimately reached by a combined strategy of pharmacological enhancement (CYP3A inhibition by fluconazole) and adjustment of dosing intervals supported by PopPK modeling, which suggested (off‐label) twice‐daily administration.

6. NOMENCLATURE OF TARGETS AND LIGANDS

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY ²¹ and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/24. ²²

AUTHOR CONTRIBUTIONS

All authors were involved in the conception, intervention, and drafting of the manuscript and its critical revision. CS and WEH designed the pharmacological intervention and drafted the manuscript. SC and LC cared for the patient. ADM developed the PopPK model and its application. JW was involved in the pharmacogenetic analysis. All authors critically reviewed the final version of this manuscript and approved its submission.

CONFLICT OF INTEREST STATEMENT

The authors have no conflict of interest or financial support to disclose.

INFORMED CONSENT

Written consent was obtained from the patient for this publication.

ETHICS STATEMENT

The patient's data were collected as part of routine care during her inpatient stay, no additional investigations were performed, and the data were summarized retrospectively, so that ethical approval was not required. The data were anonymized and published with her written consent in accordance with the COPE guidelines. ²³

ACKNOWLEDGMENTS

The authors received no support from any organization for the submitted work. Open Access funding enabled and organized by Projekt DEAL.

Scherkl C, Meid AD, Cuntz SE, et al. Coadministration of fluconazole to boost subtherapeutic sirolimus concentrations: A case report. Pharmacol Res Perspect. 2024;12:e1198. doi: 10.1002/prp2.1198

DATA AVAILABILITY STATEMENT

Data will be shared upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data will be shared upon reasonable request.

[prp21198-bib-0001] 1. Stenton SB, Partovi N, Ensom MHH. Sirolimus: the evidence for clinical pharmacokinetic monitoring. Clin Pharmacokinet. 2005;44(8):769‐786. doi: 10.2165/00003088-200544080-00001 [DOI] [PubMed] [Google Scholar]

[prp21198-bib-0002] 2. McCune JS, Bemer MJ, Long‐Boyle J. Pharmacokinetics, pharmacodynamics, and pharmacogenomics of immunosuppressants in allogeneic hematopoietic cell transplantation: part II. Clin Pharmacokinet. 2016;55(5):551‐593. doi: 10.1007/s40262-015-0340-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[prp21198-bib-0003] 3. Mizuno T, Emoto C, Fukuda T, Hammill AM, Adams DM, Vinks AA. Model‐based precision dosing of sirolimus in pediatric patients with vascular anomalies. Eur J Pharm Sci. 2017;109S:S124‐S131. doi: 10.1016/j.ejps.2017.05.037 [DOI] [PubMed] [Google Scholar]

[prp21198-bib-0004] 4. Breithaupt MH, Krohmer E, Taylor L, et al. Time course of CYP3A activity during and after metamizole (dipyrone) in healthy volunteers. Br J Clin Pharmacol. 2023;89(8):2458‐2464. doi: 10.1111/bcp.15720 [DOI] [PubMed] [Google Scholar]

[prp21198-bib-0005] 5. Cervelli MJ. Fluconazole‐sirolimus drug interaction. Transplantation. 2002;74(10):1477‐1478. doi: 10.1097/00007890-200211270-00024 [DOI] [PubMed] [Google Scholar]

[prp21198-bib-0006] 6. Wang J, Huang L, Gao P, et al. Diltiazem on tacrolimus exposure and dose sparing in Chinese pediatric primary nephrotic syndrome: impact of CYP3A4, CYP3A5, ABCB1, and SLCO1B3 polymorphisms. Eur J Clin Pharmacol. 2021;77(1):71‐77. doi: 10.1007/s00228-020-02977-y [DOI] [PubMed] [Google Scholar]

[prp21198-bib-0007] 7. Wu K, Cohen EEW, House LK, et al. Nonlinear population pharmacokinetics of sirolimus in patients with advanced cancer. CPT Pharmacometrics Syst Pharmacol. 2012;1(12):e17. doi: 10.1038/psp.2012.18 [DOI] [PMC free article] [PubMed] [Google Scholar]

[prp21198-bib-0008] 8. Leven C, Coste A, Mané C. Free and open‐source Posologyr software for Bayesian dose individualization: an extensive validation on simulated data. Pharmaceutics. 2022;14(2):442. doi: 10.3390/pharmaceutics14020442 [DOI] [PMC free article] [PubMed] [Google Scholar]

[prp21198-bib-0009] 9. Li Y, Yan L, Shi Y, Bai Y, Tang J, Wang L. CYP3A5 and ABCB1 genotype influence tacrolimus and sirolimus pharmacokinetics in renal transplant recipients. Springerplus. 2015;4:637. doi: 10.1186/s40064-015-1425-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

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