Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans

Kashyap Patel, Carl M. Kirkpatrick, Keith A. Nieforth, Sushmita Chanda, Qingling Zhang, Matthew McClure, John Fry, Julian A. Symons, Lawrence M. Blatt, Leo Beigelman, John Devincenzo, Dymphy R. Huntjens, Patrick F. Smith

Research output: Contribution to journalArticle

Abstract

Background Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5′-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. Objectives To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Methods Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay. Results The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC 50 = 1.79 μM), with >99% viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC 50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients. Conclusions The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients.

Original languageEnglish (US)
Pages (from-to)442-452
Number of pages11
JournalJournal of Antimicrobial Chemotherapy
Volume74
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Respiratory Syncytial Viruses
Nucleosides
Respiratory Syncytial Virus Infections
Prodrugs
Pharmacokinetics
Pediatrics
Population
Uridine
Therapeutic Uses
Life Cycle Stages
Viral Load
Human Influenza
Antiviral Agents
Theoretical Models
Morbidity
Mortality
Therapeutics
triphosphoric acid

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Microbiology (medical)
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans. / Patel, Kashyap; Kirkpatrick, Carl M.; Nieforth, Keith A.; Chanda, Sushmita; Zhang, Qingling; McClure, Matthew; Fry, John; Symons, Julian A.; Blatt, Lawrence M.; Beigelman, Leo; Devincenzo, John; Huntjens, Dymphy R.; Smith, Patrick F.

In: Journal of Antimicrobial Chemotherapy, Vol. 74, No. 2, 01.02.2019, p. 442-452.

Research output: Contribution to journalArticle

Patel, K, Kirkpatrick, CM, Nieforth, KA, Chanda, S, Zhang, Q, McClure, M, Fry, J, Symons, JA, Blatt, LM, Beigelman, L, Devincenzo, J, Huntjens, DR & Smith, PF 2019, 'Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans', Journal of Antimicrobial Chemotherapy, vol. 74, no. 2, pp. 442-452. https://doi.org/10.1093/jac/dky415
Patel, Kashyap ; Kirkpatrick, Carl M. ; Nieforth, Keith A. ; Chanda, Sushmita ; Zhang, Qingling ; McClure, Matthew ; Fry, John ; Symons, Julian A. ; Blatt, Lawrence M. ; Beigelman, Leo ; Devincenzo, John ; Huntjens, Dymphy R. ; Smith, Patrick F. / Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans. In: Journal of Antimicrobial Chemotherapy. 2019 ; Vol. 74, No. 2. pp. 442-452.
@article{ac7f42933cb64df9840ddc2237069b2b,
title = "Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans",
abstract = "Background Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5′-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. Objectives To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Methods Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay. Results The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC 50 = 1.79 μM), with >99{\%} viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC 50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients. Conclusions The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients.",
author = "Kashyap Patel and Kirkpatrick, {Carl M.} and Nieforth, {Keith A.} and Sushmita Chanda and Qingling Zhang and Matthew McClure and John Fry and Symons, {Julian A.} and Blatt, {Lawrence M.} and Leo Beigelman and John Devincenzo and Huntjens, {Dymphy R.} and Smith, {Patrick F.}",
year = "2019",
month = "2",
day = "1",
doi = "10.1093/jac/dky415",
language = "English (US)",
volume = "74",
pages = "442--452",
journal = "Journal of Antimicrobial Chemotherapy",
issn = "0305-7453",
publisher = "Oxford University Press",
number = "2",

}

TY - JOUR

T1 - Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans

AU - Patel, Kashyap

AU - Kirkpatrick, Carl M.

AU - Nieforth, Keith A.

AU - Chanda, Sushmita

AU - Zhang, Qingling

AU - McClure, Matthew

AU - Fry, John

AU - Symons, Julian A.

AU - Blatt, Lawrence M.

AU - Beigelman, Leo

AU - Devincenzo, John

AU - Huntjens, Dymphy R.

AU - Smith, Patrick F.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Background Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5′-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. Objectives To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Methods Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay. Results The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC 50 = 1.79 μM), with >99% viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC 50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients. Conclusions The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients.

AB - Background Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5′-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. Objectives To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Methods Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay. Results The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC 50 = 1.79 μM), with >99% viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC 50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients. Conclusions The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients.

UR - http://www.scopus.com/inward/record.url?scp=85060169363&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060169363&partnerID=8YFLogxK

U2 - 10.1093/jac/dky415

DO - 10.1093/jac/dky415

M3 - Article

VL - 74

SP - 442

EP - 452

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

IS - 2

ER -