Pharmacologic effects of oseltamivir in immunocompromised adult patients as assessed by population PK/PD analysis and drug-disease modelling for dosing regimen optimization

Abstract

Aim: Pharmacologic effects were analysed to determine a dose recommendation for oseltamivir in immunocompromised (IC) adults with influenza.

Methods: Quantitative clinical pharmacology methods were applied to data from 160 adult IC patients (aged 18-78 years) from two studies (NV20234, 150 patients; NV25118, 10 patients) who received oseltamivir 75-200 mg twice daily for up to 10 days. An established population-pharmacokinetic (PK) model with additional effects on oseltamivir and oseltamivir carboxylate (OC) clearance described the PK characteristics of oseltamivir in IC patients versus otherwise healthy (OwH) patients from previous clinical trials. Estimated PK parameters were used to evaluate exposure-response relationships for virologic endpoints (time to cessation of viral shedding, viral load measures and treatment-emergent resistance). A drug-disease model characterized the viral kinetics of influenza accounting for the effect of OC on viral production.

Results: Oseltamivir clearance was 32.5% lower (95% confidence interval [CI], 26.1-38.8) and OC clearance was 33.7% lower (95% CI, 23.2-44.1) in IC versus OwH patients. No notable exposure-response relationships were identified for exposures higher than those achieved after conventional dose oseltamivir 75 mg, which appeared to be close to the maximum effect of oseltamivir. Simulations of the drug-disease model predicted that initiating treatment within 48 hours of symptom onset had maximum impact, and a treatment duration of 10 days was favourable over 3-5 days to limit viral rebound.

Conclusions: Our findings support the use of conventional-dose oseltamivir 75 mg twice daily for 10 days in the treatment of IC adult patients with influenza.

Keywords: clinical trials; immunosuppression; modelling and simulation; pharmacokinetic-pharmacodynamic; population analysis.

FIGURE 1

(A) Oseltamivir and (B) oseltamivir carboxylate exposure (0‐12 hours) at steady state in immunocompromised adult patients (study N20234, n = 22) and previous clinical data from otherwise healthy patients (n = 306 ¹¹ , ¹² , ¹³ , ¹⁴ ). Median values are designated by black lines in the center of the boxes; boxes indicate the IQR and whiskers represent 1.5 × IQR. AUC, area under the curve; IC, immunocompromised; IQR, interquartile range; OwH, otherwise healthy

FIGURE 2

(A) Kaplan‐Meier plot for time to cessation of viral shedding (RT‐PCR) by exposure category defined by oseltamivir carboxylate C _min and (B) oseltamivir carboxylate exposure versus response for viral load (RT‐PCR). C _min, minimum plasma concentration; OC, oseltamivir carboxylate; RT‐PCR, reverse transcriptase‐polymerase chain reaction

FIGURE 3

Disease modelling simulation results showing the impact of (A) dose, (B) time from onset of symptoms to treatment initiation and (C) duration of treatment on viral load (RT‐PCR). The median AUC estimate for oseltamivir carboxylate was 5,360 ng.H/mL after 75‐mg dosing (and 10, 550 ng.H/mL after 150‐mg dosing for (A). Lines show the median percentile with shaded areas representing the 90% prediction intervals. The horizontal dashed line defines the median lower limit of quantitation (2.8 log₁₀ vp/mL) for influenza A and B viral strains. For (A) and (C), treatment was assumed to start at 2 days after symptom onset and infection was assumed to occur 36 hours before the onset of symptoms. RT‐PCR, reverse transcriptase‐polymerase chain reaction; vp, viral particles