Hydromorphone

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Prescription Opioids. VI. Metabolism and Excretion of Hydromorphone in Urine Following Controlled Single-Dose Administration

Author:

DePriest AZ, Heltsley R, Black DL, Mitchell JM, LoDico C, Flegel R, and Cone EJ

Year:

2016

Bibliographic source:

Journal of Analytical Toxicology, 40: 575–582

Materials and methods

Objective of study:

excretion

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

This study characterized the time course of the test material in hydrolysed and non-hydrolysed urine specimens. Twelve healthy subjects were administered a single 8 mg controlled-release test material dose, followed by periodic collection of pooled urine specimens for 54 h following administration. Analysis of total and free test material was conducted by liquid chromatography tandem mass spectrometry at a 50 ng/mL limit of quantitation. Detection periods were determined over a range of thresholds from 50 to 2 000 ng/mL.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hydromorphone

EC Number:

207-383-5

EC Name:

Hydromorphone

Cas Number:

466-99-9

Molecular formula:

C17H19NO3

IUPAC Name:

(1S,5R,13R,17R)-10-hydroxy-4-methyl-12-oxa-4-azapentacyclo[9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7(18),8,10-trien-14-one

Radiolabelling:

no

Test animals

Species:

other: Human

Strain:

other: Not applicable

Details on species / strain selection:

Human volunteers

Sex:

male/female

Details on test animals or test system and environmental conditions:

All subjects were healthy adult volunteers who provided informed consent and had not used opioids in the last 3 months or food products containing poppy seeds within the last week. The study was approved by an Institutional Review Board (Independent IRB, Plantation, FL, USA). Study subjects included eight males and four females, with mean age (range) of 30.2 (18–43) years and mean weight (range) of 78.7 (58.9–107.1) kg. The subjects identified themselves as follows: Eight Black or African American, three White and one Hispanic or Latino. Subject designations were numbered non-consecutively, as numbering (1 through 24) also included 12 subjects enrolled in a separate study with a difference substance conducted during the same time frame.
Initial medical and toxicology urine screening for drugs of abuse were negative. Subjects were confined at the clinic beginning the day before dosing until 54 h post-dose.
The study was conducted as a single centre, clinic-based, un-blinded study.

Administration / exposure

Route of administration:

oral: capsule

Vehicle:

unchanged (no vehicle)

Details on exposure:

Twelve volunteers were orally administered a single dose of one 8 mg test material-extended release tablet with 240 mL of room temperature water.

Duration and frequency of treatment / exposure:

Single administration

Doses / concentrations

Dose / conc.:

8 other: mg

No. of animals per sex per dose / concentration:

Twelve subjects

Control animals:

no

Positive control reference chemical:

None

Details on study design:

Liquid chromatography tandem mass spectrometry analysis
All urine specimens were analysed by Aegis Sciences Corporation by using a previously reported, validated liquid chromatography tandem mass spectrometry (LC–MS-MS) method. Urine specimens were analysed for free and total analytes following hydrolysis performed with β-glucuronidase [Type L-II, Patella vulgata (keyhole limpet)] at pH 5.0 with incubation for 18 h at 60°C. The limit of quantitation (LOQ) for all analytes was 50 ng/mL.
LOQ was determined by serial dilution of a fortified urine sample. Criteria for setting the LOQ were as follows:
(i) the response for LOQ had to be > ×10 signal/noise,
(ii) the response had to meet all qualitative criteria (as listed below) and
(iii) quantitation had to be within ± 20% of the target concentration. The upper limit of quantitation (ULOQ) was 2 000 ng/mL for all analytes. The ULOQ had to meet all qualitative criteria and measure within ± 20% of the target concentration. When an analyte exceeded the ULOQ, the specimen was diluted and re-analysed.
The percent deviation from the target concentration and inter-run imprecision [coefficient of variation (CV)] of control samples prepared in urine containing 100 ng/mL (low control) and 2 000 ng/mL (high control) concentrations of each analyte ranged as follows: For hydrolysed low control for the test material (n = 28), deviation was -4.7% and inter-run imprecision was 8.1%; for hydrolysed low control for HM-3-glucuronide (n = 36), deviation was −7.0% and inter-run imprecision was 3.9%; for hydrolysed high control for the test material (n = 24), deviation was -7.2% and inter-run imprecision was 3.9%; for non-hydrolysed low control for the test material (n = 24), deviation was -1% and inter-run imprecision was 3.6%; and for non-hydrolysed high control for the test material (n = 24), deviation was -4.4% and inter-run imprecision was 3.4%.

General criteria for identification and measurement of the analytes were as follows:
(i) relative retention time (RRT) of each analyte in the specimen had to be within ± 0.01 of the calibrator RRT or the retention time of each analyte in the sample had to be within ± 3% of its respective calibrator retention time,
(ii) ion ratios for the product ions derived from analytes and their respective internal standards in controls and donor specimens had to be within the ± 20% mean range of those obtained from the corresponding calibrator substances,
(iii) control samples were required to measure within ± 10% of the in-house determined mean value and,
(iv) negative controls could not have detectable analytes above the LOQ. All quantitative data for the drugs and metabolites in the study that met identification and quantitation (≥ LOQ) criteria were reported.

Details on dosing and sampling:

Urine specimens were collected at baseline (BL) immediately prior to dosing and as pooled collections thereafter during the following time intervals (in hours) post-dose: 0–2, 2–4, 4–6, 6–8, 8–10, 10–12, 12–14, 14–24, 24– 28, 28–32, 32–36, 36–48, 48–52 and 52–54.
Specimen volumes were measured and two 30 mL aliquots were transferred to polypropylene bottles and frozen until time of analysis.
Additional biological specimens (oral fluid and blood) were also collected but not reported on.

Statistics:

Maximum concentration (Cmax), time to maximum concentration (Tmax) and percent of dose excreted over 54 h were calculated for free and total test material, reporting mean, standard error of the mean (SEM), and range. Percent dose excreted was calculated on a molar basis to account for differences in molecular weight, using 285.338 mg/mmoL for the test material, and 321.80 mg/mmoL for the test material. Detection times were calculated based on the time to last detectable positive specimen for each subject. The last time at the end of each collection pool was used to designate time (in hours) in calculations. Data analysis was performed in Microsoft Office Excel 2010.

Results and discussion

Preliminary studies:

Twelve subjects completed the study and provided specimens for analysis. Three subjects noted mild-to-moderate adverse effects, including nausea, headache, light headedness, dry mouth, tachycardia, elevated blood pressure and redness to IV site. No serious safety events occurred.
Subject 4 reported moderate vomiting following dose administration, which resolved during the study.

Urine collections
Subjects 15 and 24 provided all requested urine specimens for the 168 planned urine pool collection periods post-dosing. The other 10 subjects were unable to produce a urine specimen during one or more of the planned collection periods. During collections, the 48–52 h pooled specimen for Subject 10 spilled and part was lost; the remaining pooled specimen for that collection interval was retained and analysed.
Two collection errors occurred for Subject 17: The urine specimen for the 2–4 h interval was inadvertently added to the 0–2 h pooled collection, and the 6–8 h urine was voided in the toilet and lost to the study. The urine volumes for Subject 22’s 48–52 h collection and Subject 23’s 14–24 h collection were not recorded. Of the 143 post-dose pooled specimens successfully collected, 95 (66 %) pooled specimens represented a single void during the collection interval.

Toxicokinetic / pharmacokinetic studies

Details on excretion:

All baseline urine specimens (pre-drug) tested negative (Total test material was detected (≥ LOQ) in 122 (85.3%) of hydrolysed urine specimens collected post-dose. Free test material was detected in 68 (47.6%) non-hydrolysed specimens for all but one subject. Mean total test material concentrations exceeded free test material by 8- to 14-fold. Total test material was initially detected at a mean ± SEM (range) of 6.3 ± 0.5 (range 4–10 h) following dosing. Initial detection of free test material was observed at a mean of 9.6 h ± 1.6 (range 6–24 h).
The test material was excreted predominantly as the conjugated metabolite, accounting for ~29% of the dose, with only minor amounts (2.7%) excreted as free test material. At the various thresholds studied, the percentage of post-dose hydrolysed specimens positive for total test material were: 7.0% at 2 000 ng/mL, 25.2% at 1 000 ng/mL, 48.3% at 500 ng/mL, 64.3% at 300 ng/mL, 76.9% at 150 ng/mL, 82.5% at 100 ng/mL and 85.3% at 50 ng/mL. In non-hydrolysed specimens, free test material was not detected above 1 000 ng/mL; detection rates at lower thresholds were 0.7% at 500 ng/mL, 4.9% at 300 ng/mL, 15.4% at 150 ng/mL and 28.7% at 100 ng/mL.
Detection times were calculated as the time from drug administration to the time of the last positive specimen, using the end of the pooled collection interval. The evaluated thresholds, ranging from 50 to 2 000 ng/mL, are employed in various settings and include the 50 and 100 ng/mL cut-offs in the proposed Mandatory Guidelines for Federal Workplace Drug Testing Programs. Analysing for total test material in hydrolysed urine extended the detection period over free test material by 1.4- to 37-fold at the different thresholds studied. Significant variability was noted between subjects; at the 500 ng/mL cut-off, three subjects were positive for total test material for 52 h, whereas test material was undetectable for Subject 12. Eleven subjects were positive for test material in hydrolysed urine at the last collected specimen, using thresholds of either 50 or 100 ng/mL.

Any other information on results incl. tables

Mean maximum urine concentration, time to maximum concentration and percent dose excreted in urine over 54 h following administration of an 8 mg dose of the test material.

Analyte	N	Cmax ± SEM (range) (ng/mL)	Tmax ± SEM (range) (h)*	Dose excreted (%) ± SEM (range) (0 – 54 h)**
Total test material	12	1 918 ± 305 (357 – 3 937)	20 ± 2 (10 – 28)	32.03 ± 2.8 (11.4 – 46.6)
Free test material	11	237 ± 47 (69 – 593)	19 ± 2 (10 – 24)	2.68 ± 0.56 (0 – 5.34)

* Estimated based on end of collection period.

** Dose exceeded (in percentage) mean and SEM calculated using data for all 12 subjects.

 

Mean ± SEM and individual range of detection times (time to last detectable positive) for test material in hydrolysed and non-hydrolysed urine specimens based on different cut-off concentrations.

Cutoff (ng/mL)	Hydrolysed* total test material detection time ± SEM (range) (h)	Non-hydrolysed** free test material detection time ± SEM (range) (h)
2 000	11.3 ± 4.1 (0 – 32)	ND
1 000	23.7 ± 3.4 (0 – 36)	ND
500	36.7 ± 4.4 (0 – 52)	1.0 ± 1.0 (0 – 12)
300	47.0 ± 2.2 (28 – 52)	6.7 ± 3.5 (0 – 32)
150	51.0 ± 1.4 (36 – 54)	16.7 ± 4.4 (0 – 36)
100	52.3 ± 0.5 (48 – 54)	26.0 ± 5.2 (0 – 52)
50	52.3 ± 0.5 (48 – 54)	38.0 ± 4.9 (0 – 52)

ND: Not Determined

* Five subjects were positive for the test material > 2 000 ng/mL at collections ending between 24 and 32 h, 10 subjects were positive for the test material ≥ 1 000 ng/mL at collections ending between 24 and 36 h and 11 subjects were positive for the test material ≥ 500 ng/mL at collections ending between 24 and 52 h.

** One subject was positive for the test material ≥ 500 ng/mL at 12 h, two subjects were positive for the test material ≥ 300 ng/mL at collections ending between 24 and 32 h, seven subjects were positive for the test material ≥ 150 ng/mL at collections ending between 24 and 36 hand nine subjects were positive for the test material ≥ 100 ng/mL at collections ending between 24 and 52 h.

Applicant's summary and conclusion

Conclusions:

Under the conditions of the study, 28% and 2% of the dose administered was detected in the urine as total and free-test material respectively. The period of detection ranged from 11 to 52 hours over the thresholds studied, with the maximum detection period observed for both 50 and 100 ng/mL cut-offs.

Executive summary:

The study characterised the time course of the test material in hydrolysed and non-hydrolysed urine specimens. Twelve healthy subjects were administered a single 8 mg controlled-release test material dose, followed by periodic collection of pooled urine specimens for 54 h following administration. Analysis of total and free test material was conducted by liquid chromatography tandem mass spectrometry at a 50 ng/mL limit of quantitation. Detection periods were determined over a range of thresholds from 50 to 2 000 ng/mL.

Under the conditions of the studyt the test material was detected in 85.3% and 47.6% of hydrolysed and non-hydrolysed post-dose specimens, respectively. Initial detection of total test material was frequently observed in the first 4–6 h following dosing. The period of detection at the 50 ng/mL threshold averaged 52.3 h for total test material and 38.0 h for free test material.