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Clinical Trial Details — Status: Withdrawn

Administrative data

NCT number NCT01123486
Other study ID # STU00013543
Secondary ID
Status Withdrawn
Phase N/A
First received May 10, 2010
Last updated April 21, 2015
Start date January 2015
Est. completion date January 2015

Study information

Verified date April 2015
Source Northwestern University
Contact n/a
Is FDA regulated No
Health authority United States: Institutional Review Board
Study type Interventional

Clinical Trial Summary

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.


Description:

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.


Recruitment information / eligibility

Status Withdrawn
Enrollment 0
Est. completion date January 2015
Est. primary completion date January 2015
Accepts healthy volunteers Accepts Healthy Volunteers
Gender Both
Age group 21 Years to 30 Years
Eligibility Inclusion Criteria:

- 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.)

Exclusion Criteria:

- 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

Study Design

Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment


Related Conditions & MeSH terms


Intervention

Drug:
hydromorphone
hydromorphone 0.02 mg/kg

Locations

Country Name City State
United States Northwestern Memorial Hospital Chicago Illinois

Sponsors (1)

Lead Sponsor Collaborator
Northwestern University

Country where clinical trial is conducted

United States, 

References & Publications (46)

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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. — View Citation

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. — View Citation

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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. — View Citation

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. doi: 10.1038/clpt.2008.80. Epub 2008 May 7. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Maitre PO, Stanski DR. Bayesian forecasting improves the prediction of intraoperative plasma concentrations of alfentanil. Anesthesiology. 1988 Nov;69(5):652-9. — View Citation

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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. — View Citation

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. — View Citation

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. — View Citation

Minto CF, Schnider TW, Shafer SL. Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. Anesthesiology. 1997 Jan;86(1):24-33. — View Citation

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. — View Citation

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. — View Citation

Scott JC, Cooke JE, Stanski DR. Electroencephalographic quantitation of opioid effect: comparative pharmacodynamics of fentanyl and sufentanil. Anesthesiology. 1991 Jan;74(1):34-42. — View Citation

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. — View Citation

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. — View Citation

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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. — View Citation

Shafer SL, Stanski DR. Improving the clinical utility of anesthetic drug pharmacokinetics. Anesthesiology. 1992 Mar;76(3):327-30. — View Citation

Shafer SL, Varvel JR, Aziz N, Scott JC. Pharmacokinetics of fentanyl administered by computer-controlled infusion pump. Anesthesiology. 1990 Dec;73(6):1091-102. — View Citation

Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics, and rational opioid selection. Anesthesiology. 1991 Jan;74(1):53-63. — View Citation

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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. — View Citation

* Note: There are 46 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary Opioid induced analgesia A combined PK-PD model for hydromorphone induced analgesia (heat pain tolerance) will be developed 24 hours No
Secondary Opioid induced ventilatory depression A combined PK-PD model for hydromorphone induced ventilatory depression will be created 24 hours Yes
Secondary Opioid induced miosis A combined PK-PD model for hydromorphone induced miosis will be developed 24 hours No
Secondary Opioid induced EEG changes A combined PK-PD model for hydromorphone induced EEG effects will be developed 24 hours No
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