Development and physico-chemical stability study of an oral liquid form of letermovir for pediatric use

Sabri A, Bari L, Vasseur V, Le Liboux J, Benakouche S, Bourdon O, Storme T
Pharmacotechnie pédiatrique, Pharmacie à usage intérieur, Hôpital universitaire mère-enfants Robert Debré, APHP.Nord, 48 Bld Sérurier 75019 Paris – France

Introduction
Cytomegalovirus (CMV) infection is a major complication of transplantation in hematopoietic stem cell (HSC) recipients. Among the new therapies available, letermovir (LMV) has an interesting safety profile. The currently available oral forms of LMV (PREVYMIS®, 240 and 480mg tablets) are not suitable for pediatric use.

Objectives
Validate a Stability-indicating assay method, develop an oral liquid form (OLF) of LMV suitable for pediatrics and evaluate its physico-chemical stability.

Material and method
Pediatric dosages were evaluated by extrapolation from adult dosages. As LMV is not available in the form of pharmaceutical raw powder, the OLF is prepared from crushed PREVYMIS® tablets suspended in InOrpha®.
We evaluated the degradation, the organoleptic characteristics, the pH, the osmolarity, are evaluated.
The assay is performed by HPLC-UV (C18 grafted column, mobile phase: ammonium carbonate 1.92 g/L (pH =7.9) / acetonitrile (40/60: v/v)). The Stability-indicating assay method is validated according to GERPAC recommendations and after forced degradation tests by UV, HCl, NaOH and H2O2. The calibration range was performed with 3 calibration standards 25, 50 and 75 µg/mL.
The stability was studied on finished product (n=3) at 5±3°C and 20±5°C, over 1 month with daily opening of the vials and 3 months without opening.

Results
The OLF dosed at 20 mg/mL in Inorpha is packaged in amber glass bottles. The formulation allows for easy dosage adjustment in pediatrics. We did not achieve complete solubilization of LMV. However, the observed sedimentation can be resuspended easily. The FOL retains the same appearance in terms of coloration and pH (= 4.9).
The assay is linear (R²> 0.99), accurate (recovery rate < 1%), repeatable (CV < 1%), and faithful (CV < 5%). No matrix effect was detected (pvalue > 0.05). The relative deviation of the concentration from the D0 concentration did not exceed +/- 10%. The developed oral suspension is stable for 1 month at 5±3°C and 20±5°C (with and without opening).

Conclusion
This OLF of letermovir responds to a real need in pediatric HSC recipient patients. The use of InOrpha® avoids exposure to excipients with notable effects and its low osmolarity (≈ 180 mOsm/kg) is compatible with a fragile gastrointestinal tract. The assay method is accurate and reproducible according to GERPAC recommendations.

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