# The need for area under the curve measurements in the field of ganciclovir therapeutic drug monitoring in children: a case report

Xavier Duval, Florian Lemaitre, Sophie Pertuisel, Jamie Probert, Virginie Gandemer, Marie-Clémence Verdier, Camille Tron

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Xavier Duval, Florian Lemaitre, Sophie Pertuisel, Jamie Probert, Virginie Gandemer, et al. The need for area under the curve measurements in the field of ganciclovir therapeutic drug monitoring in children: a case report. BMC Infectious Diseases, 2021, 21 (1), 10.1186/s12879-021-06828-8. hal-03439332

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# The need for area under the curve measurements in the field of ganciclovir therapeutic drug monitoring in children: a case report

Xavier Duval<fnref n="1" />, Florian Lemaitre<fnref n="1" />,², Sophie Pertuisel³, Jamie Probert³, Virginie Gandemer³, Marie-Clémence Verdier<fnref n="1" />,² and Camille Tron<fnref n="1" />,²*

**Abstract**

**Background:** Ganciclovir pharmacokinetics is characterized by a high variability in drug exposure. Usually, monitoring of ganciclovir exposure is performed by measuring trough concentration. However, due to the specificity of pediatric pharmacokinetics, trough concentration measurements may not be a relevant surrogate of ganciclovir exposure. Area under the curve of concentration (AUC) may be a more appropriate biomarker.

**Case presentation:** We report the case of a 3.6-year-old boy with Emberger syndrome with a cytomegalovirus reactivation occurring after allogenic hematopoietic stem cell transplantation. After a few days of treatment with intravenous ganciclovir, sub-therapeutic trough ganciclovir concentrations were measured (< 0.5 µg/mL) and viral load still increased. Ganciclovir dosage was increased by two-fold to deal with this treatment failure. Trough concentrations remained sub-therapeutic. The patient had hematologic disorder therefore it was decided to estimate ganciclovir AUC to assess more accurately drug exposure before any further dosage modification. AUC₀−₁₂h was measured at 51 µg h/mL, which was within the therapeutic range (40–60 µg h/mL). Afterward, viral load decreased and became undetectable.

**Conclusions:** This case report highlights that monitoring ganciclovir exposure based on AUC should be performed to tailor drug dosage in order to improve treatment efficacy and safety in pediatric patients.

**Keywords:** Therapeutic drug monitoring, Antiviral therapy, Cytomegalovirus (CMV), Pharmacokinetics, Hematopoietic stem cell transplantation, Pediatrics

**Background**

Ganciclovir is the treatment of choice for Cytomegalovirus (CMV) reactivation in immunocompromised patients [1]. Its pharmacokinetics is characterized by a high interpatient variability [2, 3]. Therefore, therapeutic drug monitoring (TDM) of ganciclovir is valuable to

individualize dosing regimens [4]. Measuring trough concentration ($C_0$) in plasma is the standard approach as a proxy for the antiviral drug exposure. Area under the curve of concentration versus time (AUC) measurements is considered to be the best surrogate for drug exposure. However this parameter is rarely used for ganciclovir TDM in clinical practice while population pharmacokinetic modeling removed practical huddles that used to limit access to AUC-based TDM [5]. Due to the specificity of pediatric pharmacokinetics, trough

<footnote>*Correspondence: camille.tron@chu-rennes.fr</footnote>

<footnote n="1">¹ Laboratory of Clinical Pharmacology, University Hospital of Rennes, 2 Rue Henri le Guilloux, 35000 Rennes, France
Full list of author information is available at the end of the article</footnote>
concentration measurements may not be a relevant expo-
sure biomarker for ganciclovir and AUC evaluation may
be more appropriate in this context [2–4].

Case presentation

To emphasize this statement, we report the case of a
3.6-year-old boy with Emberger syndrome. This syn-
drome is associated with an increased risk of myelodys-
plastic syndrome, familial acute myeloid leukemia and
immune deficiency. Therapeutic management is limited
to prophylactic antimicrobial treatment and pre-emptive
allogenic hematopoietic stem cell transplantation (allo-
genic HSCT).

In June 2020, the patient received an allogenic hap-
loidentical HSCT. After transplantation, he received
ciclosporine, mycophenolic acid and post-transplant
cyclophosphamide as immunosuppressive therapy. In
addition, prednisone was introduced at day-21 post
transplantation to treat grade 3 acute graft-versus host
disease and 5 days later ruxolitinib was introduced
because of progression. Posaconazole was also started
at day-26 and cotrimoxazole as a prophylaxis of pneu-
mocystosis at day-48. Thirty-four days after transplanta-
tion, a CMV reactivation was diagnosed with a positive
CMV viral load at 3.52 log copies/mL. Intravenous gan-
ciclovir was introduced (5 mg/kg q12h; 70 mg q12h) to

prevent morbidity and mortality of the infection in this
clinical setting. At the same period, pancytopenia has
been observed and might have been worsened by several
of the drugs received by the patient including ganciclo-
vir. The patient was then administered G-CSF injections
every 3 days. After 3 weeks of ganciclovir treatment, the
viral load did not decrease (Fig. 1). Low drug exposure
and UL97 or UL54 virological resistance were suspected.
Through ganciclovir concentrations were sub-therapeutic
(< 0.5 µg/mL) (Fig. 1) and the resistance mutation analy-
sis was negative meaning that treatment failure was likely
due to drug underexposure. The patient had a rapid renal
clearance (creatinine clearance (CrCl): 220.5 mL/min
using Schwartz formula [6]) so it was decided to con-
duct an AUC-driven ganciclovir dosage adaptation. The
dosage was thus increased to 10 mg/kg q12h (140 mg
q12h). Exposure was assessed by collecting five plasma
concentrations between drug intakes and AUC<sub>0-12 h</sub> was
estimated using a non-compartmental approach based
on five sampling times: pre-dose, and then 1, 2, 4 and 6 h
post-dose). As displayed in Fig. 1, whereas trough con-
centrations remained below the usual therapeutic thresh-
old (e.g. < 0.5 µg/mL) [7–9] peak concentrations was high
and AUC<sub>0-12 h</sub> was close to 50 µg h/mL, which was within
the therapeutic range (40–60 µg h/mL) suggested by
some authors to treat CMV infection [10, 11]. Eventually,

<figure><img src="image_3.png" /><figcaption>**Fig. 1** Course of CMV viral load and GCV concentrations. *HSCT* hematopoietic stem-cell transplantation, *GCV* Ganciclovir, *CMV* Cytomegalovirus, *C*₀ trough concentration, *AUC* area under the curve concentration</figcaption></figure>
viral load decreased quickly after 6 days at this dosage and became undetectable after 52 days. Two months later, viral load has remained undetectable. No significant change in the haematological parameters was noted after ganciclovir dosage modification.

## Discussion and conclusions

This case report emphasizes that TDM of ganciclovir is highly relevant to improve treatment efficacy in the setting of CMV pediatric infection. Standard dosage based on body weight is not a relevant strategy to deal with the high inter-patient variability of ganciclovir pharmacokinetics in pediatrics given the rapid drug clearance in this sub-population [2]. During the 3-weeks period without TDM, ganciclovir exposure was low in this child and CMV replication was not controlled. For practical reasons, TDM is usually based only on the measurement of trough plasma concentration since AUC calculation requires to collect several blood samples. Invasiveness of this approach can be a hurdle to its implementation. However, some teams showed that AUC can be used for TDM in clinical practice complementarily to trough or peak concentrations [5]. In addition, after allogenic HSCT, patients benefit from in-patient monitoring and samples can be collected through a central line. As reported by other teams [4, 9], in this patient, trough concentrations appeared poorly correlated to AUC. Indeed, after dosage adjustment, trough concentrations minimally changed while therapeutic AUC₀−₁₂ h was obtained. This is a key point since ganciclovir dosage would have probably been increased beyond 10 mg/kg to reach the target therapeutic range of trough concentrations (≥ 0.5 to 3 µg/mL) [7–9]. In pediatric patient, dosing ganciclovir according to trough concentrations may then preclude safety of the drug. Although the threshold of AUC associated with toxicity is not fully elucidated [12], the corresponding AUC₀−₁₂ h would certainly have been very high (above 60 µg h/mL) resulting in a potential exacerbation of the pancytopenia. AUC measurements allowed dealing with the clinical issue, which was reaching a negative viremia while limiting hematologic disorders coming from ganciclovir overexposure. This case report highlights that monitoring ganciclovir exposure based on AUC should be performed to tailor drug dosage in pediatric patients. It is a useful tool for clinician to increase treatment success and to prevent adverse events.

## Abbreviations

CMV: Cytomegalovirus; TDM: Therapeutic drug monitoring; C₀: Trough concentration; AUC: Area under the curve of concentration versus time; allogenic HSCT: Allogenic hematopoietic stem cell transplantation; CrCl: Creatinine clearance.

## Acknowledgements

Not applicable.

## Authors' contributions

XD: conceptualization, writing-original draft, validation, visualization. FL: conceptualization, writing-original draft, validation, supervision. SP, JP, VG: resources, writing—review and editing. MCV: writing—review and editing, validation, supervision. CT: conceptualization, writing-original draft, validation, supervision. All authors read and approved the final manuscript.

## Funding

This research did not receive any specific grant, all data have been generated as part of the routine work of University Hospital of Rennes.

## Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

## Declarations

### Ethics approval and consent to participate

Not applicable.

### Consent for publication

The parents gave their written consent for their child's personal or clinical details along with any identifying images to be published in this study.

### Competing interests

The authors declare that they have no known competing interests or personal relationships that could have appeared to influence the work reported in this paper.

### Author details

¹Laboratory of Clinical Pharmacology, University Hospital of Rennes, 2 Rue Henri le Guilloux, 35000 Rennes, France. ²Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, University of Rennes, 35000 Rennes, France. ³Department of Paediatric Hemato-Oncology, University Hospital of Rennes, 35000 Rennes, France.

Received: 28 June 2021 Accepted: 28 October 2021

Published online: 08 November 2021

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