Reporting Guidelines for Clinical Pharmacokinetic Studies: the Clinpk Statement

Reporting Guidelines for Clinical Pharmacokinetic Studies: The ClinPK Statement

Electronic Supplementary Material

Salmaan Kanji, BSc.Pharm, Pharm.D.

The Ottawa Hospital and Ottawa Hospital Research Institute

Meghan Hayes, BSc.Pharm.

The Ottawa Hospital

Adam Ling, Pharm.D. Candidate

University of Waterloo

Larissa Shamseer, PhD candidate

The Ottawa Hospital Research Institute

University of Ottawa

Clarence Chant, Pharm.D., BCPS, FCCP FCSHP

St. Micheal’s Hospital, Toronto

Leslie Dan Faculty of Pharmacy, University of Toronto

David J. Edwards, BScPhm, PharmD, MPH

School of Pharmacy, University of Waterloo

Scott Edwards, Pharm.D.

Eastern Health, Memorial University of Newfoundland

Mary HH Ensom, Pharm.D., FASHP, FCCP, FCSHP, FCAHS

Faculty of Pharmaceutical Sciences, University of British Columbia

Pharmacy Department, Children’s & Women’s Health Centre of British Columbia

David R. Foster, Pharm.D., FCCP

College of Pharmacy, Purdue University

Brian Hardy, Pharm.D.

Sunnybrook Health Sciences Center, Toronto

Leslie Dan Faculty of Pharmacy, University of Toronto

Tyree H. Kiser, Pharm.D.

Department of Clinical Pharmacy, University of Colorado

Charles la Porte, PharmD, PhD

Janssen-Cilag BV. Tilburg, The Netherlands

Jason A. Roberts, PhD, B Pharm(Hons), FSHP

Burns Trauma and Critical Care Research Centre, The University of Queensland

Royal Brisbane and Women’s Hospital

Institute of Translational Medicine, The University of Liverpool

Rob Shulman DHC(Pharm)

University College London Hospitals NHS Trust

Scott Walker, Pharm.D.

Sunnybrook Health Science Center, Toronto, Ontario, Canada

Sheryl Zelenitsky, BSc.Pharm., PharmD

College of Pharmacy, University of Manitoba

David Moher, PhD

The Ottawa Hospital Research Institute

Faculty of Medicine, University of Ottawa

Corresponding Author: Salmaan Kanji, Pharm.D.

c/o Department of Pharmacy

The Ottawa Hospital

501 Smyth Rd

Ottawa, Ontario, Canada

K1H 8L6

Table S1: Characteristics of 68 Expert Panellists

None(%) / Poor(%) / Average(%) / Good(%)
Self-rated knowledge of clinical pharmacokinetics / 0 (0) / 0 (0) / 26 (38%) / 42 (62%)
Perspective [n (%)]
Clinical pharmacokinetic researcher / 50 (74)
Knowledge user / 50 (74)
Country of employment [n (%)]
Canada / 36 (53)
United States / 17 (25)
The Netherlands / 4 (6)
The United Kingdom / 3 (4)
Australia / 2 (3)
Germany / 2 (3)
France / 2 (3)
Finland / 1 (1)
Greece / 1 (1)
Primary employer [n (%)]
University / 28 (41)
Hospital / 29 (43)
Research Institute / 6 (9)
Pharmaceutical Industry / 5 (7)

Table S2: Examples of compliant reporting by item

Checklist Item # / Example
Title/Abstract
1 / “Population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension.”
Reference: Vezina HE, Ng CM, Vazquez DM, Barks JD, Bhatt-Mehta V. Population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension. Pediatric critical care medicine 2014;15:546-53.
2 / “OBJECTIVES: To determine the population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants receiving IV hydrocortisone for treatment of vasopressor-resistant hypotension and to identify patient-specific sources of pharmacokinetic variability.
DESIGN: Prospective observational cohort study.
SETTING: Level 3 neonatal ICU.
PATIENTS: Sixty-two critically ill neonates and infants receiving IV hydrocortisone as part of standard of care for the treatment of vasopressor-resistant hypotension: median gestational age 28 weeks (range, 23-41), median weight 1.2 kg (range, 0.5-4.4), and 29 females.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Unbound baseline cortisol and postdose hydrocortisone concentrations measured from blood samples being drawn for routine laboratory tests. A one-compartment model best described the data. Allometric weight and postmenstrual age were significant covariates on unbound hydrocortisone clearance and volume of distribution. Final population estimates for clearance, volume of distribution, and baseline cortisol concentration were 20.2 L/hr, 244 L, and 1.37 ng/mL, respectively. Using the median weight and postmenstrual age of our subjects (i.e., 1.2 kg and 28 wk) in the final model, the typical unbound hydrocortisone clearance and volume of distribution were 1.0 L/hr and 4.2 L, respectively. The typical half-life for unbound hydrocortisone was 2.9 hours. A sharp and continuous increase in unbound hydrocortisone clearance was observed at 35 weeks postmenstrual age.
CONCLUSIONS: We report the first pharmacokinetic data for unbound hydrocortisone, the pharmacologically active moiety, in critically ill neonates and infants with vasopressor-resistant hypotension. Unbound hydrocortisone clearance increased with body weight and was faster in children with an older postmenstrual age. Unbound hydrocortisone clearance increased sharply at 35 weeks postmenstrual age and continued to mature thereafter. This study lays the groundwork for evaluating unbound hydrocortisone exposure-response relationships and drawing definitive conclusions about the dosing of IV hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension.”
Reference: Vezina HE, Ng CM, Vazquez DM, Barks JD, Bhatt-Mehta V. Population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension. Pediatric critical care medicine 2014;15:546-53.
Background
3 / “Fenofibrate is a prodrug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the liver to fenofibric acid, which is the active constituent measurable in the circulation. After oral administration in healthy volunteers, peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration. After absorption, ~60% of a single dose of radiolabeled fenofibrate is excreted in the urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% is excreted in the feces.”
Reference: Chachad SS, Gole M, Malhotra G, Naidu R. Comparison of pharmacokinetics of two fenofibrate tablet formulations in healthy human subjects. Clinical therapeutics 2014;36:967-73.
4 / “Several reformulations of fenofibrate dominate the market, although generic fenofibrate has been available for almost a decade. This continued use of branded formulations, which cost twice as much as generic versions of fenofibrate, imposes a high cost on the health care system. It is hence essential that low-cost yet equally effective and safe drug formulations are made available. In anticipation of the patent expiry, a pharmaceutical equivalent to the marketed fenofibrate 145-mg tablets was developed (by Cipla Limited, Mumbai, India).”
Reference: Chachad SS, Gole M, Malhotra G, Naidu R. Comparison of pharmacokinetics of two fenofibrate tablet formulations in healthy human subjects. Clinical therapeutics 2014;36:967-73.
5 / “The objective of the present study was to compare the pharmacokinetics and safety of 2 tablet formulations containing 145 mg of fenofibrate (CAS number 49562-28-9) in healthy human subjects.”
Reference: Chachad SS, Gole M, Malhotra G, Naidu R. Comparison of pharmacokinetics of two fenofibrate tablet formulations in healthy human subjects. Clinical therapeutics 2014;36:967-73.
Methods
6 / “Subjects were enrolled according to their degree of renal function based on their estimated GFR (eGFR), determined using the four-variable Modification of Diet in Renal Disease Formula. The four parallel groups of subjects were healthy subjects with normal renal function (eGFR [80 mL/min); subjects with mild renal impairment (eGFR C50 to 80 mL/min); subjects with moderate renal impairment (eGFR C30 to\50 mL/min); and patients with endstage renal disease (ESRD) (eGFR\30 mL/min, currently receiving dialysis). The subjects were males and nonpregnant, non-lactating females aged 18–80 years old, with a body mass index between 19 and 40 kg/m2 and a body weight of at least 50 kg.
Subjects were required to be free from clinically significant medical, including neurologic or psychiatric, disease, and to have no clinically relevant abnormalities in clinical laboratory tests or ECGs, other than those associated with their degree of renal impairment. Subjects were excluded if they had any clinically significant abnormal vital signs, a history of suicide attempts, a history of gastrointestinal surgery, an active renal transplant, a history of or an ongoing severe allergy or hypersensitivity, or were current users of nicotine. Subjects with a positive result from screening for serum hepatitis B surface antigen of HIV were excluded. Female subjects were required to be postmenopausal, surgically sterilized, or using a highly effective form of birth control from 3 months prior to enrolment until 3 months post-dosing of study drug. Male subjects were also required to use an accepted double barrier form of contraceptive.”
Reference: Alverlind S, Barassin S, Dalen P, et al. Clinical pharmacokinetics of the nicotinic channel modulator dexmecamylamine (TC-5214) in subjects with various degrees of renal impairment. Clin Drug Investig 2014;34:457-65.
7 / “Use of drugs that could potentially influence study results was not allowed; however, subjects could continue their routine medications as long as the medical condition was stable and there had been no significant alterations in the medical regimen within 6 weeks (subjects with normal renal function) to 1 month (subjects with renal insufficiency) before receiving the dose of dexmecamylamine…
…. two treatment periods separated by a 14-day washout period. All doses were given with 240 mL of water and subjects were required to fast from 2 h prior to dosing until 1 h post-dose.”
Reference: Alverlind S, Barassin S, Dalen P, et al. Clinical pharmacokinetics of the nicotinic channel modulator dexmecamylamine (TC-5214) in subjects with various degrees of renal impairment. Clin Drug Investig 2014;34:457-65.
8 / “In the postanaesthetic care unit, when patients had fully recovered from general anaesthesia (tracheal tube removed) or when the anaesthetic level of spinal anaesthesia was below T10, 20 mg of nefopam hydrochloride (Acupan® injectable; Biocodex, Montrouge, France; IUPAC name, 5-methyl-1-phenyl-1,3,4,6-tetrahydro-2,5-benzoxazocine) diluted with 0.9% of saline solution was infused over a 30 min period using an infusion pump.”
Reference: Djerada Z, Fournet-Fayard A, Gozalo C, et al. Population pharmacokinetics of nefopam in elderly, with or without renal impairment, and its link to treatment response. Br J Clin Pharmacol 2014;77:1027-38.
9 / “Blood samples were collected from the antecubital vein in heparinized tubes before dosing and at the following times: 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12 and 24 h. Blood samples were centrifuged immediately after collection at 3500 rpm for 10 min. Plasma samples were transferred directly into plain plastic tubes and immediately stored at –20 °C pending analysis.”
Reference: Badawi MA, Wagdy E, Nasr M, Etman MA, El-Khordagui LK, Khalil SA. Postmarketing pharmacokinetic and pharmacodynamic equivalence of generic and brand atenolol in Egypt. Eastern Mediterranean health journal 2014;19 Suppl 3:S166-71.
10 / “Atenolol concentrations in plasma samples were determined after protein precipitation using a sensitive and reproducible HPLC method with fluorometric detection, as described previously. Metoclopramide was used as the internal standard (IS). All chemicals and reagents were of analytical grade and solvents were of HPLC grade.
An Agilent Laboratories HPLC device, 1200 Series (Santa Clara, CA, USA) was used for analysis. The device was equipped with a Zobrax extend HPLC C18 column (150 × 4.6 mm; 5-μm particle size; Agilent). The isocratic mobile phase consisted of water and methanol (85:15), 0.05% triethylamine, and was adjusted to pH 3 with phosphoric acid. The flow rate was set at 0.8 mL/min, and the separated samples were detected using a fluorescence detector maintained at λex 229 nm and λem 300 nm.
A stock standard solution of atenolol (1 mg/mL) was prepared in methanol and a stock IS solution of metoclopramide (1 mg/mL) was prepared in a methanol: water mixture (1:1). Working standard solutions were prepared by appropriate dilution in methanol. Solutions were protected from light and stored at –20 °C.
Plasma sample aliquots (1 mL) were vortex-mixed with 200 μL IS [1 mg/mL) and 200 μL trichloroacetic acid (TCA); 55%, final concentration 7.86%] for 20 s, followed by centrifugation at 3500 rpm for 20 min. The supernatant was filtered using a 0.45-μm Millipore filter (EMD Millipore, USA) and 200 μL of the filtrate was injected.
Atenolol recovery was calculated by comparing peak areas for standard samples in spiked plasma before and after the preparation procedure. The stability of atenolol in TCA was assessed by comparing chromatograms of atenolol dissolved in either methanol or TCA.
The following parameters were determined: specificity, linearity, accuracy, precision, and limit of quantification. Specificity was checked by comparing chromatograms of blank plasma and plasma samples containing atenolol and the IS following sample preparation. Linearity was assessed by constructing a calibration curve of atenolol in spiked plasma at a concentration range of 25–800 ng/mL. Inter-day accuracy and precision were determined by analysis of spiked plasma samples at three different atenolol concentrations (50, 200 and 800 ng/mL) on three consecutive days. Data for intra-day accuracy and precision were obtained by six replicate analyses carried out on the same day. The relative standard deviation should be within ± 15%. The limit of quantification of atenolol was determined by calculating the amount of drug exhibiting a signal:noise ratio of 10:1.”
Reference: Badawi MA, Wagdy E, Nasr M, Etman MA, El-Khordagui LK, Khalil SA. Postmarketing pharmacokinetic and pharmacodynamic equivalence of generic and brand atenolol in Egypt. Eastern Mediterranean health journal 2014;19 Suppl 3:S166-71.
11 / “…Pharmacokinetic parameters [maximum (peak) steady-state plasma drug concentration (Cmax,ss), area under the plasma concentration–time curve during dosing interval (AUCτ,ss)] for gemigliptin, LC15-0636 (active metabolite of gemigliptin), and metformin were calculated using the non-compartmental method of WinNonlin® version 6.2 (Pharsight Corporation, Cary, NC, USA).”
Reference: Shin D, Cho YM, Lee S, et al. Pharmacokinetic and pharmacodynamic interaction between gemigliptin and metformin in healthy subjects. Clin Drug Investig 2014;34:383-93.
12 /
Reference: Struemper H, Sale M, Patel BR, et al. Population pharmacokinetics of ofatumumab in patients with chronic lymphocytic leukemia, follicular lymphoma, and rheumatoid arthritis. Journal of clinical pharmacology 2014;54:818-27.
13 / “…The secondary pharmacokinetic parameters—the elimination constant from the body (k10) and the area under the serum concentration–time curve (AUC)—were estimated from the primary parameters according to Eqs. 2 and 3:
t½ = 0.693 × Vd
CL
AUC = Dose
CL
where t½ is the elimination half-life. …”
Reference: Getts DR, Kramer WG, Wiseman AC, Flechner SM. The pharmacokinetics and pharmacodynamics of TOL101, a murine IgM anti-human alphabeta T cell receptor antibody, in renal transplant patients. Clin Pharmacokinet 2014;53:649-57.
14 / “Piperacillin [35 mg/kg actual body weight (ABW)] was injected IV over 5 …
Clearance calculations and GFR were normalized to a body surface area of 1.73 m2. Body surface area was determined by the following formula: {[ABW (kg) × height (cm)]/3600}1/2.”
Reference: Manley HJ, Bailie GR, Frye R, McGoldrick MD. Intermittent intravenous piperacillin pharmacokinetics in automated peritoneal dialysis patients. Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis 2000;20:686-93.
15 / “Demographic data are expressed as median (range) and were analysed using a two-tailed unpaired t-test. Pharmacokinetic data analysis used the R data analysis and statistical language (Version 2.10.1) using a single factor ANOVA [21]. Values were expressed as mean (±SD), or as mean (range) depending on their distribution.”
Reference: Dooney NM, Sundararajan K, Ramkumar T, et al. Pharmacokinetics of tramadol after subcutaneous administration in a critically ill population and in a healthy cohort. BMC anesthesiology 2014;14:33.
Results
16 / “Sixteen participants were enrolled, with eight randomized to each of the dapivirine and placebo vaginal ring arms. Fifteen participants completed the trial; one participant assigned to placebo ring was hospitalized on day 30, 2 days after the ring was removed on day 28, and the subsequent final trial visit was not conducted. The participant was diagnosed with a congenital deficiency in the TOLL-like receptor 3 (TLR3), which led to various episodes of uncontrolled infections and hospitalization.
The eight participants assigned to the dapivirine ring were included in the pharmacokinetic analyses, and all 16 enrolled participants were included in the safety analyses.”
Reference: Nel A, Haazen W, Nuttall J, Romano J, Rosenberg Z, van Niekerk N. A safety and pharmacokinetic trial assessing delivery of dapivirine from a vaginal ring in healthy women. Aids 2014;28:1479-87.
17 / “Missing continuous infusion durations (for two occasions in the model development dataset) were assumed to be 16 h, per protocol. No other imputation of dosing information was conducted for the model development dataset. For the external evaluation dataset, missing dosing information on the pharmacokinetic sampling days was imputed from the days prior to pharmacokinetic sampling since dosing was to be stable during this period (309 out of the 311 subjects had imputed dosing at least on one occasion). Missing body weight values for two subjects in the external evaluation dataset were imputed with 70 kg (which approximated the median body weight in the dataset). All levodopa concentrations in the development and evaluation datasets were above the limit of quantitation.”
Reference: Othman AA, Dutta S. Population pharmacokinetics of levodopa in subjects with advanced Parkinson's disease: levodopa-carbidopa intestinal gel infusion vs. oral tablets. Br J Clin Pharmacol 2014;78:94-105.
18 /

Reference: Goyal N, Beerahee M, Kalberg C, Church A, Kilbride S, Mehta R. Population pharmacokinetics of inhaled umeclidinium and vilanterol in patients with chronic obstructive pulmonary disease. Clin Pharmacokinet 2014;53:637-48.
19 /

Reference: Kim A, Chung I, Yoon SH, et al. Effects of proton pump inhibitors on metformin pharmacokinetics and pharmacodynamics. Drug Metab Dispos 2014;42:1174-9.
20 / “Blood samples were drawn from the prefilter (arterial) and postfilter (venous) lines of the extracorporeal circuit at 0, 30, 60, 90, 180, 360, 480, and 1,440 min after finishing the infusion. Regarding tolerability and occurrence of hematological side effects, red blood cells (RBC), hemoglobin (HB), platelets (PLT) and white blood cells (WBC) were quantified on a daily basis during the treatment phase.
Ultradiafiltrate samples were taken from the outlet of the ultradiafiltrate compartment of the hemodiafilter at the corresponding times…
…CVVHDF was performed by using an AN 69 HF hollow-fiber hemofilter (Prisma M100 Pre Set; Hospal Industrie, Meyzieu, France) with a membrane surface area of 0.9 m2. Dialyzers and lines were steam sterilized. The standard blood flow rate was 9 liters/h, the predilution volume was infused at a rate of 1 liter/h, and the dialysate rate was 1 liter/h, as described previously. Net fluid balance was modified according to clinical requirements. No filter change occurred during the study period.”
Reference: Horvatits T, Kitzberger R, Drolz A, et al. Pharmacokinetics of ganciclovir during continuous venovenous hemodiafiltration in critically ill patients. Antimicrob Agents Chemother 2014;58:94-101.
21 /