Hydromorphone Pharmacokinetic-Pharmacodynamic Fingerprint
Information source: Northwestern University
Information obtained from ClinicalTrials.gov on December 08, 2011
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Pain; Ventilatory Depression
Intervention: hydromorphone (Drug)
Sponsored by: Northwestern University
Official(s) and/or principal investigator(s):
Dhanesh K. Gupta, M.D., Principal Investigator, Affiliation: Departments of Anesthesiology & Neurological Surgery, Northwestern University Feinberg School of Medicine
Dhanesh K Gupta, M.D., Phone: 312-926-8369, Email: firstname.lastname@example.org
The primary objective of the proposed work is development of a high resolution
pharmacokinetic-pharmacodynamic (PK-PD) model of hydromorphone for experimental pain
stimuli, ventilatory depression, and surrogate biomarkers of opioid effect that will allow
the fingerprinting of hydromorphone. This fingerprint will serve as the basis for the
development of dosing strategies that efficiently maximize analgesia while minimizing
ventilatory depression and sedation. For example, this high-resolution fingerprint will
allow precise estimation of an initial hydromorphone target effect site concentration (Ce)
from those of effectively administered synthetic opioids with previously determined
high-resolution fingerprints (i. e., remifentanil or fentanyl), thereby minimizing
underdosing of hydromorphone for analgesia and minimizing side effects.
Official title: A Hydromorphone High Resolution Pharmacokinetic-Pharmacodynamic Fingerprint as the Basis for Identifying Sex Differences in Opioid Pharmacokinetics and Pharmacodynamics
Study design: Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Opioid induced analgesia
Opioid induced miosis
Opioid induced EEG changes
Secondary outcome: Opioid induced ventilatory depression
After 6 h of fasting, each volunteer will have a 20G arterial-line placed in the radial
artery for early blood sampling and an 18 G peripheral intravenous catheter placed in the
contralateral forearm for drug administration and later blood sampling. Continuously
monitored vital signs will include ECG, invasive blood pressure, hemoglobin, O2 saturation,
end-tidal CO2, and respiratory rate (from the capnogram) recorded.
After baseline PD data acquisition, a bolus of 0. 2 mg/kg hydromorphone will be administered
over 10 sec via the free-flowing peripheral IV (t=0) and 3 mL arterial blood samples will be
obtained at 0. 25, 0. 5, 0. 75, 1, 1. 25, 1. 5, 1. 75, and 2 min using a stop-cock and manifold
system. Subsequent blood samples will be acquired at 3, 4, 5, 7. 5, 10, 15, 20, 25, 30, and
45 min and 1, 1. 25, 1. 5, 2, 2. 25, 2. 5, 2. 75, 3, 3. 5, 4, 4. 5, 5, 6, 7, 8, 10, 12, 16, 20, and
24 h. Although EEG will be acquired continuously, the remaining pharmacologic data will be
recorded at discrete times s in the initial 5 min: pupillometry at 1, 2, and 5 min;
ventilation at 2 min; temperature analgesia at 3 and 5 min, and sedation level at 4 min.
This will allow the ventilation and pupillometry to be acquired in a resting state, thereby
limiting distortion of these responses by stimulation. Subsequently, all data will be
acquired at all PK time points in the following sequence - ventilation and EEG
(simultaneously), pupillometry, modified OAA/S score, and temperature analgesia. After 2 h,
once a pharmacologic parameter has returned to baseline for 2 sequential measurements,
recording of that parameter will be stopped. During the study, if the volunteer is unable to
use the device trigger, due to opioid-induced sedation, the tolerance level for increased
temperature will be defined as the temperature at which the volunteer exhibits withdrawal
movement of the tested limb. Once all data acquisition has been completed, the volunteer
will be allowed to drink clear liquids. Subsequently, the diet will be advanced as
tolerated. The volunteer will be monitored hourly (vital signs) in the Clinical Research
Unit until all of the blood samples have been acquired.
Minimum age: 21 Years.
Maximum age: 30 Years.
- within 20% of their ideal body weight
- 21-30 years old
- ASA I (no systemic disease)
- No history of PONV (except wisdom teeth extraction)
- No long term medication use
- No history of coagulation defect (i. e easy bruising, gum bleeding with teeth
brushing, frequent nose bleeds, past documented coagulopathy, etc.)
- Inability to place an arterial line
- A failed urine drug test on admission to the CRU
- A positive pregnancy test on admission to the CRU
- A hemoglobin level < 12. 5 g/dL on admission to the CRU
Locations and Contacts
Dhanesh K Gupta, M.D., Phone: 312-926-8369, Email: email@example.com
Northwestern Memorial Hospital, Chicago, Illinois 60611, United States; Recruiting
Dhanesh K Gupta, M.D., Principal Investigator
Upton RN, Semple TJ, Macintyre PE. Pharmacokinetic optimisation of opioid treatment in acute pain therapy. Clin Pharmacokinet. 1997 Sep;33(3):225-44. Review.
Stanski DR, Hug CC Jr. Alfentanil--a kinetically predictable narcotic analgesic. Anesthesiology. 1982 Dec;57(6):435-8. No abstract available.
Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology. 1985 Mar;62(3):234-41.
Maitre PO, Vozeh S, Heykants J, Thomson DA, Stanski DR. Population pharmacokinetics of alfentanil: the average dose-plasma concentration relationship and interindividual variability in patients. Anesthesiology. 1987 Jan;66(1):3-12.
Scott JC, Stanski DR. Decreased fentanyl and alfentanil dose requirements with age. A simultaneous pharmacokinetic and pharmacodynamic evaluation. J Pharmacol Exp Ther. 1987 Jan;240(1):159-66.
Scott JC, Cooke JE, Stanski DR. Electroencephalographic quantitation of opioid effect: comparative pharmacodynamics of fentanyl and sufentanil. Anesthesiology. 1991 Jan;74(1):34-42.
Björkman S, Wada DR, Stanski DR, Ebling WF. Comparative physiological pharmacokinetics of fentanyl and alfentanil in rats and humans based on parametric single-tissue models. J Pharmacokinet Biopharm. 1994 Oct;22(5):381-410. Erratum in: J Pharmacokinet Biopharm 1995 Aug;23(4):438.
Egan TD, Minto CF, Hermann DJ, Barr J, Muir KT, Shafer SL. Remifentanil versus alfentanil: comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. Anesthesiology. 1996 Apr;84(4):821-33. Erratum in: Anesthesiology 1996 Sep;85(3):695.
Minto CF, Schnider TW, Egan TD, Youngs E, Lemmens HJ, Gambus PL, Billard V, Hoke JF, Moore KH, Hermann DJ, Muir KT, Mandema JW, Shafer SL. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology. 1997 Jan;86(1):10-23.
Minto CF, Schnider TW, Shafer SL. Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. Anesthesiology. 1997 Jan;86(1):24-33.
Egan TD, Lemmens HJ, Fiset P, Hermann DJ, Muir KT, Stanski DR, Shafer SL. The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology. 1993 Nov;79(5):881-92.
Segre G. Kinetics of interaction between drugs and biological systems. Farmaco Sci. 1968 Oct;23(10):907-18. No abstract available.
Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J. Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther. 1979 Mar;25(3):358-71.
Ebling WF, Lee EN, Stanski DR. Understanding pharmacokinetics and pharmacodynamics through computer stimulation: I. The comparative clinical profiles of fentanyl and alfentanil. Anesthesiology. 1990 Apr;72(4):650-8.
Gregg KM, Varvel JR, Shafer SL. Application of semilinear canonical correlation to the measurement of opioid drug effect. J Pharmacokinet Biopharm. 1992 Dec;20(6):611-35.
Lemmens HJ, Dyck JB, Shafer SL, Stanski DR. Pharmacokinetic-pharmacodynamic modeling in drug development: application to the investigational opioid trefentanil. Clin Pharmacol Ther. 1994 Sep;56(3):261-71.
Lemmens HJ, Egan TD, Fiset P, Stanski DR. Pharmacokinetic/dynamic assessment in drug development: application to the investigational opioid mirfentanil. Anesth Analg. 1995 Jun;80(6):1206-11.
Kern SE, Stanski DR. Pharmacokinetics and pharmacodynamics of intravenously administered anesthetic drugs: concepts and lessons for drug development. Clin Pharmacol Ther. 2008 Jul;84(1):153-7. Epub 2008 May 7. Review.
Ausems ME, Vuyk J, Hug CC Jr, Stanski DR. Comparison of a computer-assisted infusion versus intermittent bolus administration of alfentanil as a supplement to nitrous oxide for lower abdominal surgery. Anesthesiology. 1988 Jun;68(6):851-61.
Maitre PO, Ausems ME, Vozeh S, Stanski DR. Evaluating the accuracy of using population pharmacokinetic data to predict plasma concentrations of alfentanil. Anesthesiology. 1988 Jan;68(1):59-67.
Maitre PO, Stanski DR. Bayesian forecasting improves the prediction of intraoperative plasma concentrations of alfentanil. Anesthesiology. 1988 Nov;69(5):652-9.
Raemer DB, Buschman A, Varvel JR, Philip BK, Johnson MD, Stein DA, Shafer SL. The prospective use of population pharmacokinetics in a computer-driven infusion system for alfentanil. Anesthesiology. 1990 Jul;73(1):66-72. Erratum in: Anesthesiology 1990 Oct;73(4):798.
Shafer SL, Varvel JR, Aziz N, Scott JC. Pharmacokinetics of fentanyl administered by computer-controlled infusion pump. Anesthesiology. 1990 Dec;73(6):1091-102.
Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics, and rational opioid selection. Anesthesiology. 1991 Jan;74(1):53-63.
Shafer SL, Gregg KM. Algorithms to rapidly achieve and maintain stable drug concentrations at the site of drug effect with a computer-controlled infusion pump. J Pharmacokinet Biopharm. 1992 Apr;20(2):147-69.
Fiset P, Mathers L, Engstrom R, Fitzgerald D, Brand SC, Hsu F, Shafer SL. Pharmacokinetics of computer-controlled alfentanil administration in children undergoing cardiac surgery. Anesthesiology. 1995 Nov;83(5):944-55.
Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology. 1992 Mar;76(3):334-41.
Shafer SL, Stanski DR. Improving the clinical utility of anesthetic drug pharmacokinetics. Anesthesiology. 1992 Mar;76(3):327-30. No abstract available.
Dahan A, Romberg R, Teppema L, Sarton E, Bijl H, Olofsen E. Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion. Anesthesiology. 2004 Nov;101(5):1201-9.
Dershwitz M, Walsh JL, Morishige RJ, Connors PM, Rubsamen RM, Shafer SL, Rosow CE. Pharmacokinetics and pharmacodynamics of inhaled versus intravenous morphine in healthy volunteers. Anesthesiology. 2000 Sep;93(3):619-28.
Coda B, Tanaka A, Jacobson RC, Donaldson G, Chapman CR. Hydromorphone analgesia after intravenous bolus administration. Pain. 1997 May;71(1):41-8.
Gourlay GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology. 1982 Dec;57(6):458-67. No abstract available.
Ausems ME, Hug CC Jr, Stanski DR, Burm AG. Plasma concentrations of alfentanil required to supplement nitrous oxide anesthesia for general surgery. Anesthesiology. 1986 Oct;65(4):362-73.
Bouillon T, Bruhn J, Radu-Radulescu L, Andresen C, Cohane C, Shafer SL. A model of the ventilatory depressant potency of remifentanil in the non-steady state. Anesthesiology. 2003 Oct;99(4):779-87.
Vuyk J, Lim T, Engbers FH, Burm AG, Vletter AA, Bovill JG. Pharmacodynamics of alfentanil as a supplement to propofol or nitrous oxide for lower abdominal surgery in female patients. Anesthesiology. 1993 Jun;78(6):1036-45; discussion 23A.
Billard V, Gambus PL, Chamoun N, Stanski DR, Shafer SL. A comparison of spectral edge, delta power, and bispectral index as EEG measures of alfentanil, propofol, and midazolam drug effect. Clin Pharmacol Ther. 1997 Jan;61(1):45-58.
Phimmasone S, Kharasch ED. A pilot evaluation of alfentanil-induced miosis as a noninvasive probe for hepatic cytochrome P450 3A4 (CYP3A4) activity in humans. Clin Pharmacol Ther. 2001 Dec;70(6):505-17.
Kharasch ED, Hoffer C, Walker A, Sheffels P. Disposition and miotic effects of oral alfentanil: a potential noninvasive probe for first-pass cytochrome P4503A activity. Clin Pharmacol Ther. 2003 Mar;73(3):199-208.
Kharasch ED, Walker A, Hoffer C, Sheffels P. Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: noninvasive assessment by use of pupillary miosis. Clin Pharmacol Ther. 2004 Nov;76(5):452-66.
Baririan N, Van Obbergh L, Desager JP, Verbeeck RK, Wallemacq P, Starkel P, Horsmans Y. Alfentanil-induced miosis as a surrogate measure of alfentanil pharmacokinetics in patients with mild and moderate liver cirrhosis. Clin Pharmacokinet. 2007;46(3):261-70.
Davis JJ, Swenson JD, Hall RH, Dillon JD, Johnson KB, Egan TD, Pace NL, Niu SY. Preoperative "fentanyl challenge" as a tool to estimate postoperative opioid dosing in chronic opioid-consuming patients. Anesth Analg. 2005 Aug;101(2):389-95, table of contents. Erratum in: Anesth Analg. 2005 Oct;101(4):965.
Angst MS, Chu LF, Tingle MS, Shafer SL, Clark JD, Drover DR. No evidence for the development of acute tolerance to analgesic, respiratory depressant and sedative opioid effects in humans. Pain. 2009 Mar;142(1-2):17-26. Epub 2009 Jan 9.
Manyam SC, Gupta DK, Johnson KB, White JL, Pace NL, Westenskow DR, Egan TD. Opioid-volatile anesthetic synergy: a response surface model with remifentanil and sevoflurane as prototypes. Anesthesiology. 2006 Aug;105(2):267-78.
Manyam SC, Gupta DK, Johnson KB, White JL, Pace NL, Westenskow DR, Egan TD. When is a bispectral index of 60 too low?: Rational processed electroencephalographic targets are dependent on the sedative-opioid ratio. Anesthesiology. 2007 Mar;106(3):472-83.
Barrett PH, Bell BM, Cobelli C, Golde H, Schumitzky A, Vicini P, Foster DM. SAAM II: Simulation, Analysis, and Modeling Software for tracer and pharmacokinetic studies. Metabolism. 1998 Apr;47(4):484-92.
Kuipers JA, Boer F, Olofsen E, Bovill JG, Burm AG. Recirculatory pharmacokinetics and pharmacodynamics of rocuronium in patients: the influence of cardiac output. Anesthesiology. 2001 Jan;94(1):47-55.
Starting date: May 2010
Last updated: January 5, 2011