An Open-label, Single-dose Study to Evaluate the Pharmacokinetics, Biotransformation and Excretion of [¹⁴C]AMG 416 in Patients With End Stage Renal Disease Receiving Dialysis
Overview
- Phase
- Phase 1
- Intervention
- [¹⁴C]Etelcalcetide
- Conditions
- Secondary Hyperparathyroidism in Patients With ESRD on Hemodialysis
- Sponsor
- Amgen
- Enrollment
- 6
- Locations
- 1
- Primary Endpoint
- Time to Maximum Observed Concentration (Tmax) of [¹⁴C]Etelcalcetide-derived Radioactivity in Plasma
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
The primary objectives of this study were to determine the rate, extent, and routes of radioactivity excretion of [¹⁴C]etelcalcetide in feces, dialysate, and urine over time and to measure radioactivity concentrations in whole blood and plasma over time.
Detailed Description
Six adult male or female patients with end stage renal disease requiring hemodialysis will be enrolled to receive 750 nCi of \[¹⁴C\]-labeled etelcalcetide formulated in 10 mg etelcalcetide administered as a single 2 mL intravenous dose at the end of hemodialysis. Participants will spend the first approximately 12 days in confinement at the clinic (day -1 until completion of day 11 study procedures). Blood samples, and complete collections of dialysate, dialysis membrane (as necessary), urine (as available), and feces will be analyzed for radioactivity content by accelerator mass spectrometry (AMS). Following the confinement period, participants will return to the site on an outpatient basis in accordance to their routine dialysis sessions up to day 39. Blood and dialysate samples and dialysis membranes will be collected at specified times during the outpatient visit period. Participants may be asked to return so the site for the Extended Pharmacokinetic Collection Period. During the Extended Pharmacokinetic Collection Period, participants will return to the site for 3 consecutive hemodialysis sessions (Collection Period 1) and then again approximately one month later, for an additional 3 consecutive hemodialysis sessions (Collection Period 2).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subject has provided informed consent prior to initiation of any study-specific activities/procedures.
- •Male or female subject ≥ 18 years of age at the time of screening, with end stage renal disease receiving hemodialysis;
- •Body mass index is between 18 and 38 kg/m², inclusive;
- •Corrected calcium (calculated) level is \> 8.3 mg/dL and intact parathyroid hormone (PTH) level is between 300 - 1200, inclusive; all other laboratory tests within clinically acceptable range to the investigator and sponsor at screening;
- •Female subjects must be of non-reproductive potential (ie, postmenopausal by history - no menses for 1 year and follicle-stimulating hormone (FSH) level consistent with postmenopausal status; OR history of hysterectomy; OR history of bilateral tubal ligation);
- •Negative screen for potential drugs of abuse at screening, unless positive result is expected based on approved concomitant medications;
- •Negative alcohol test at screening;
- •Subject has functioning permanent dialysis access via fistula, hemodialysis (HD) catheter, or arteriovenous (AV) graft;
- •Subject must be receiving hemodialysis 3 times weekly for at least 1 year prior to day -1 (or is confirmed to be anuric based on historical and clinical assessment if on hemodialysis for less than one year), and have adequate hemodialysis with a delivered Kt/V ≥ 1.2 or urea reduction ratio (URR) ≥ 65% within 4 weeks to screening. The subject's routine hemodialysis session must be of 3-4.5 hours in duration, inclusive;
- •Subject has stable dialysis prescription and this prescription is not anticipated to change significantly during the course of the study.
Exclusion Criteria
- •Female subjects who are lactating/breastfeeding or who plan to breastfeed while on study through 3 months after receiving the dose of study drug;
- •Females with a positive pregnancy test at screening;
- •Positive for human immunodeficiency virus (HIV) at screening or known diagnosis of acquired immune deficiency syndrome (AIDS);
- •Positive Hepatitis B Surface Antigen (HepBsAg) at screening (indicative of chronic Hepatitis B);
- •Positive for Hepatitis C virus ribonucleic acid (RNA) by polymerase chain reaction (PCR) at screening (indicative of active hepatitis C - screening is generally done by hepatitis C antibody (HepCAb), followed by hepatitis C virus RNA by PCR if HepCAb is positive);
- •Previous administration of AMG 416;
- •Previous administration of any \[¹⁴C\] labeled drug substance within 1 year before study drug administration;
- •Subject has received cinacalcet within the 30 days prior to study drug administration (treatment with cinacalcet is prohibited during the study);
- •Subject has known sensitivity to any of the products or components to be administered during dosing;
- •Use of concomitant medication other than that used in the management of end stage renal disease and its expected comorbidities that could in the opinion of the investigator or Amgen medical monitor interfere with the safety of subjects or interpretation of study results;
Arms & Interventions
[¹⁴C]Etelcalcetide
Participants received a single dose of 10 mg radiolabelled etelcalcetide administered by intravenous (IV) bolus injection at the end of hemodialysis on day 1.
Intervention: [¹⁴C]Etelcalcetide
Outcomes
Primary Outcomes
Time to Maximum Observed Concentration (Tmax) of [¹⁴C]Etelcalcetide-derived Radioactivity in Plasma
Time Frame: Samples were collected from pre-dose on day 1 to day 39; additional samples were collected at 3 consecutive hemodialysis sessions from days 129 -148 and approximately 1 month later at an additional 3 consecutive hemodialysis sessions from days 157-176.
Total radioactive counts in plasma was determined by accelerator mass spectrometry (AMS).
Maximum Observed Concentration (Cmax) of [¹⁴C]Etelcalcetide-derived Radioactivity in Plasma
Time Frame: Samples were collected from pre-dose on day 1 to day 39; additional samples were collected at 3 consecutive hemodialysis sessions from days 129 -148 and approximately 1 month later at an additional 3 consecutive hemodialysis sessions from days 157-176.
Last Observed Plasma Concentration (Clast) of [¹⁴C]Etelcalcetide-derived Radioactivity in Plasma
Time Frame: Samples were collected from pre-dose on day 1 to day 39; additional samples were collected at 3 consecutive hemodialysis sessions from days 129 -148 and approximately 1 month later at an additional 3 consecutive hemodialysis sessions from days 157-176.
Cumulative Excretion of Radioactivity
Time Frame: Day 1 to day 176
The total radioactivity in excreta (urine and feces) or dialysate and dialysis membrane is expressed as a percentage of the total radioactive \[¹⁴C\] administered (dose). Total radioactive counts in dialysate, dialyzer, feces, and urine were determined by accelerator mass spectrometry (AMS). Radioactivity excreted during non-sampled days was estimated by interpolation and extrapolation of the measured data.
Area Under the Arterial Plasma Concentration-time Curve Obtained During Hemodialysis on Day 4 for Etelcalcetide
Time Frame: Day 4 within 10 minutes after the start of hemodialysis, at 2 hours after the start of hemodialysis, and within 10 minutes before the end of hemodialysis.
Etelcalcetide plasma concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Area Under the Venous Plasma Concentration-time Curve Obtained During Hemodialysis on Day 4 for Etelcalcetide
Time Frame: Day 4 within 10 minutes after the start of hemodialysis, at 2 hours after the start of hemodialysis, and within 10 minutes before the end of hemodialysis.
Etelcalcetide plasma concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Time to Last Observed Plasma Concentration of [¹⁴C]Etelcalcetide-derived Radioactivity in Plasma
Time Frame: Samples were collected from pre-dose on day 1 to day 39; additional samples were collected at 3 consecutive hemodialysis sessions from days 129 -148 and approximately 1 month later at an additional 3 consecutive hemodialysis sessions from days 157-176.
Apparent Terminal Half-life (T½) of [¹⁴C]Etelcalcetide-derived Radioactivity in Plasma
Time Frame: Samples were collected from pre-dose on day 1 to day 39; additional samples were collected at 3 consecutive hemodialysis sessions from days 129 -148 and approximately 1 month later at an additional 3 consecutive hemodialysis sessions from days 157-176.
Area Under the Curve From Time Zero to 3 Days Post-dose (AUC3d) of [¹⁴C]Etelcalcetide-derived Radioactivity in Plasma
Time Frame: Samples were collected from pre-dose on day 1 to day 39; additional samples were collected at 3 consecutive hemodialysis sessions from days 129 -148 and approximately 1 month later at an additional 3 consecutive hemodialysis sessions from days 157-176.
Area Under the Curve From Time Zero to 10 Days Post-dose (AUC10d) of [¹⁴C]Etelcalcetide-derived Radioactivity in Plasma
Time Frame: Samples were collected from pre-dose on day 1 to day 39; additional samples were collected at 3 consecutive hemodialysis sessions from days 129 -148 and approximately 1 month later at an additional 3 consecutive hemodialysis sessions from days 157-176.
Secondary Outcomes
- Time to Last Observed Plasma Concentration of Etelcalcetide(Samples were collected from pre-dose on day 1 to day 39; additional samples were collected at 3 consecutive hemodialysis sessions from days 129 -148 and approximately 1 month later at an additional 3 consecutive hemodialysis sessions from days 157-176.)
- Last Observed Plasma Concentration (Clast) of Etelcalcetide(Samples were collected from pre-dose on day 1 to day 39; additional samples were collected at 3 consecutive hemodialysis sessions from days 129 -148 and approximately 1 month later at an additional 3 consecutive hemodialysis sessions from days 157-176.)
- Area Under the Curve From Time Zero to 3 Days Post-dose (AUC3d) of Etelcalcetide(Samples were collected from pre-dose on day 1 to day 39; additional samples were collected at 3 consecutive hemodialysis sessions from days 129 -148 and approximately 1 month later at an additional 3 consecutive hemodialysis sessions from days 157-176.)
- Hemodialysis Clearance of Etelcalcetide During Hemodialysis on Day 4(Day 4 within 10 minutes after the start of hemodialysis, at 2 hours after the start of hemodialysis, and within 10 minutes before the end of hemodialysis.)
- Time to Maximum Observed Concentration (Tmax) of Etelcalcetide(Samples were collected from pre-dose on day 1 to day 39; additional samples were collected at 3 consecutive hemodialysis sessions from days 129 -148 and approximately 1 month later at an additional 3 consecutive hemodialysis sessions from days 157-176.)
- Maximum Observed Concentration (Cmax) of Etelcalcetide(Samples were collected from pre-dose on day 1 to day 39; additional samples were collected at 3 consecutive hemodialysis sessions from days 129 -148 and approximately 1 month later at an additional 3 consecutive hemodialysis sessions from days 157-176.)
- Hemodialysis Extraction Ratio for Etelcalcetide During Hemodialysis on Day 4(Day 4 within 10 minutes after the start of hemodialysis, at 2 hours after the start of hemodialysis, and within 10 minutes before the end of hemodialysis.)
- Number of Participants With Adverse Events(From first dose of etelcalcetide to day 39)
- Number of Participants With Anti-etelcalcetide Antibodies(Day -1 and day 39)
- Area Under the Curve From Time Zero to 10 Days Post-dose (AUC10d) of Etelcalcetide(Samples were collected from pre-dose on day 1 to day 39; additional samples were collected at 3 consecutive hemodialysis sessions from days 129 -148 and approximately 1 month later at an additional 3 consecutive hemodialysis sessions from days 157-176.)