Optimizing CMV therapy: Population pharmacokinetics and Monte Carlo simulations for letermovir and maribavir dosage

Figures

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  Fig 1. Probability of target attainment (PTA) for different trough plasma concentration higher than inhibitory concentration or 5 times PA-IC50 across different dosing regimens for letermovir (A) and maribavir (B and C). Abbreviations: A: PTA for letermovir administered without co-treatment by CsA across the range of PA-IC50 to 5 * PA-IC50, with a dose of 480 mg without a loading dose and 960 mg with a loading dose; B: PTA for maribavir across the range of PA-IC50 to 5 * PA-IC50; C: PTA for maribavir across the range of PA-IC50. The blue dashed lines represent the PA-IC50 ranges, specifically [0.047–0.092] mg/L for letermovir and [2.560–10.530] mg/L for maribavir. The red dashed lines represent the 5 * PA-IC50 ranges, specifically [0.235–0.460] mg/L for letermovir and [11.290–52.670] mg/L for maribavir. The grey solid line represents the proportion of 90% success. Recommended dose regimens are 480 mg/day and 240 mg/day administered orally or as an intravenous infusion over 1 hour respectively for letermovir without and with co-treatment by CsA, and 400 mg BID administered orally for maribavir.

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  Fig 2. Letermovir simulations for 1,000 patients for different loading doses schemes (after a typical 480 mg/daily dose, without CsA co-treatment). Abbreviations: A: without loading dose; B: loading dose on day 1 of initiation treatment, C: loading dose on day 1- day 2 of initiation treatment, D: loading dose from day1 to day 3 1 of initiation treatment. The red dashed lines represent the 5 * PA-IC50range.

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  Fig 3. Letermovir simulations for 1,000 patients for 3 different dosing resumption regimens (after a typical 480 mg/day dose and without cyclosporine co-treatment). Abbreviations: A: Dosing resumption at normal posology; B: Dosing resumption with a double dose; C: Dosing resumption with normal posology BID. The red dashed lines represent the 5 * PA-IC50range.

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  Fig 4. PTA for different trough concentration higher than inhibitory concentration or 5 times PA-IC50 after different treatment resumption scenarii following a missed dose for letermovir (A) and maribavir (B). The blue dashed lines represent the IC50 ranges, specifically [0.047–0.092] mg/L for letermovir and [2.560–10.530] mg/L for maribavir. The red dashed lines represent the 5 * PA-IC50 ranges, specifically [0.235–0.460] mg/L for letermovir and [11.290–52.670] mg/L for maribavir. The grey solid line represents the proportion of 90% success.