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EASL 2018 FRI-323
Pharmacokinetics and pharmacodynamics modeling of ritonavir
boosted lonafarnib therapy in HDV patients: A phase 2 LOWRHDV-
3 study
P. Dubey1, C. Koh2, P. Surana2, S. Uprichard1, M.A.T. Han2, N. Fryzek2,
G. Subramanya1, D. Kapuria2, O. Etzion3, V. Takyar2, Y. Rotman2,
C. Yurdaydin4, J. Glenn5, S. Cotler5, T. Heller2, H. Dahari1. 1Loyola
University Medical Center, United States; 2Liver Diseases Branch, NIDDK,
NIH, United States; 3Soroka University Medical Center, Israel; 4University
of Ankara Medical School, Turkey; 5Stanford University School of
Medicine, United States
Email: [email protected]
Background & Aim: The prenylation inhibitor lonafarnib (LNF) has
proven anti-hepatitis D virus (HDV) activity in recent phase 2 clinical
trials. The phase 2 LOWR HDV-3 study conducted with an all-oral
combination of once-daily ritonavir (RTV) boosted LNF was reported
safe and tolerable in patients for up to 6 months of therapy. In the
current study, we sought to model RTV-boosted LNF pharmacokinetics
(PK) and pharmacodynamics (PD) parameters using data from
the LOWR HDV-3 study.
Methods: HDV-infected patients were randomized in LOWR HDV-3
into one of six groups: LNF 50/75/100 mg + RTV 100 mg once daily for
24 weeks (n = 12) or 12 weeks of placebo followed by LNF 50/75/
100 mg + RTV 100 mg once daily for 12 weeks (n = 9). Since frequent
hepatitis B surface antigen (HBsAg), RTV, LNF and HDV RNA kinetics
(0, 6,12,18, 24, 36 hrs, 2, 3, 7,14, 21, 28, 56, 84,112,140,168 days)were
available in the 24 week arm of LNF 50/75/100 mg + RTV 100 mg, 12
patients in this arm were included in the modeling analysis. All
patients were treated with hepatitis B nucleotide analogues. A
modeling framework that includes proliferation of uninfected and
infected cells and accounts for LNF concentration, HDV RNA, alanine
aminotransferase (ALT) and HBsAg kinetics was used to estimate the
LNF PK and PD parameters. The standard Emax model was used to
account for the time-dependent LNF effectiveness in blocking HDV
production.
Results: While HBsAg levels did not change on therapy, four patterns
of HDV RNA response were seen in each dosing group: responders
(triphasic (n = 3), flat-partial responders (n = 3), rebound (n = 3)) and
non-responders (n = 3). ALT normalization was observed in all
triphasic and 2 (out of 3) flat-partial responders. In all 12 patients,
a transient increase in RTV concentrationwas observed with median
(interquartile range, IQR) peak Cmax_RTV = 880 (993)ng/ml during the
first week after initiation of therapy followed by a set point of 257
(297)ng/ml from week 2 onwards. Interestingly, Cmax_RTV >1200 ng/
ml was associated with the triphasic response (1 in each LNF dosing
group) in which there was a continuous HDV decline on treatment.
Based on all 12 patients, the LNF-PK model predicted a median LNF
elimination rate ke = 0.7 (0.3)/day, absorption rate ka = 9.2 (23.7) /day,
and bioavailable fraction F = 1012.7 (682.7) ng/ml. There was no
association between PK parameters and response to therapy (p ≥
0.145). LNF-PD modeling in the 9 responders suggests a median LNF
EC50 of 289 (422) ng/ml, at which LNF’s effectiveness in blocking
viral production reaches to half of its maximum, with Hill coefficient
n = 1.48.
Conclusions: Modeling daily ritonavir boosted lonafarnib indicates a
lower average LNF elimination rate (0.76/day) compared to twice a
day unboosted LNF (1.08/day – Hepatology Communications 2017;
1:288–292), which confirms the role of ritonavir to maintain high
LNF efficacy under low and daily LNF dosing with minimal side
effects.
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