Reporting Guidelines for Clinical Pharmacokinetic Studies: The

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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
[email protected]
Table S1: Characteristics of 68 Expert Panellists
None(%)
0 (0)
Self-rated knowledge of clinical
pharmacokinetics
Perspective [n (%)]
Clinical pharmacokinetic researcher
Knowledge user
Country of employment [n (%)]
Canada
United States
The Netherlands
The United Kingdom
Australia
Germany
France
Finland
Greece
Primary employer [n (%)]
University
Hospital
Research Institute
Pharmaceutical Industry
Poor(%)
0 (0)
50 (74)
50 (74)
36 (53)
17 (25)
4 (6)
3 (4)
2 (3)
2 (3)
2 (3)
1 (1)
1 (1)
28 (41)
29 (43)
6 (9)
5 (7)
Average(%)
26 (38%)
Good(%)
42 (62%)
Table S2: Examples of compliant reporting by item
Checklist Example
Item #
Title/Abstract
1
“Population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants with vasopressorresistant hypotension.”
2
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.
“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 patientspecific 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 vasopressorresistant 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.”
4
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.
“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).”
5
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.
“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;34:45765.
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.”
8
9
10
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;34:45765.
“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-2,5benzoxazocine) 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.
“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.
“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.”
11
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.
“…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
13
14
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.
“…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.
“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.”
15
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.
“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
17
“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.
“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
20
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.
“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
Reference: Martinez-Saguer I, Cicardi M, Suffritti C, et al. Pharmacokinetics of plasma-derived C1-esterase inhibitor
after subcutaneous versus intravenous administration in subjects with mild or moderate hereditary angioedema: the
PASSION study. Transfusion 2014;54:1552-61.
Discussion/Conclusion
22
“The study has a number of limitations. The small sample size precluded subgroup analyses, the aetiology of liver
cirrhosis was not uniform across the patient group and the inclusion criteria were retrospectively found to be too
wide. This latter point resulted in the inclusion of two patients whose data could not be used for determining the
association between fasting bile acids and propranolol exposure after oral administration. However during the study
planning and recruitment period, the effect of cyclosporine on the bile salt export pump and the CYP 1A2 inhibiting
effects of ciprofloxacin were not known. Similarly, it cannot be ruled out that other currently unknown factors which
affect serum bile concentrations or propranolol clearance may have been present in some individuals. Patients with
cirrhosis are known to be particularly vulnerable to the effects of drug-drug interactions. As the patients in this study
represented a mixed group with differing underlying causes of liver cirrhosis, we believe, however, that the findings
are generalisable to other patients with liver cirrhosis.”
Reference: Taegtmeyer AB, Haschke M, Tchambaz L, et al. A study of the relationship between serum bile acids and
propranolol pharmacokinetics and pharmacodynamics in patients with liver cirrhosis and in healthy controls. PLoS
One 2014;9:e97885.
23
“In conclusion, patients with liver cirrhosis had an increased exposure to propranolol after both iv and oral
application, with exposure after oral application being six-fold higher than in healthy controls who received the
same dose. This increase was explained by a greater bioavailability in the case of oral application as well as a
decreased elimination of propranolol. There was a significant linear correlation between the serum bile acid
concentration and propranolol exposure in patients without interacting co-medication. This correlation may be of
use to clinicians in selecting the optimal initial dose of oral propranolol so that adverse reactions can be avoided.
The clinical value of SBA-guided initial propranolol-dosing in patients with cirrhosis should be demonstrated in a
prospective clinical study. Whether similar correlations between fasting SBA and drug-disposition exist for other high
hepatic extraction drugs also requires further investigation.”
Reference: Taegtmeyer AB, Haschke M, Tchambaz L, et al. A study of the relationship between serum bile acids and
propranolol pharmacokinetics and pharmacodynamics in patients with liver cirrhosis and in healthy controls. PLoS
One 2014;9:e97885.
Other Information
24
“The study was supported by internal funds from the Department of Clinical Pharmacology and Toxicology,
University Hospital Basel, a grant from the Swiss National Science Foundation to SK (SNF 31003A-
132992; http://www.snf.ch/) and an unrestricted award from the Department of Internal Medicine, University
Hospital Basel (‘Astra-Fonds’). The funders had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript…
…The authors have declared that no competing interests exist.”
Reference: Taegtmeyer AB, Haschke M, Tchambaz L, et al. A study of the relationship between serum bile acids and
propranolol pharmacokinetics and pharmacodynamics in patients with liver cirrhosis and in healthy controls. PLoS
One 2014;9:e97885.
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