Pharmacokinetics of Prednisone in Adults
Pharmacokinetics of Prednisone in Adults
This is a monocentric study, in the Internal Medicine Service of Cochin Hospital, Paris. Our
 main objective is to determine the pharmacokinetic properties of prednisone, secondary
 objectives are to determine the covariates affecting the prednisone pharmacokinetics and the
 relationship between glucocorticoid exposition levels and their side effects. The
 investigators will use a prospective, observational, population pharmacokinetic approach. 100
 patients starting a prednisone treatment >7,5mg/d for an expected period >3 months will be
 recruited and followed over 6 months.
OBJECTIVES Main objective Describe the pharmacokinetic of prednisone when administered to
 adult patients in the setting of an internal medicine service.

 Secondary objectives To identify individual vulnerability factors (renal and hepatic
 functions, albuminemia, age, comedications) and glucocorticoid tolerance factors in adults.

 To study the association between individual exposition and glucocorticoids' frequent and
 clinically significative side effects.

 METHOD Conduct of research Population follow up Clinical and biological data will be
 collected through an observational prospective mono-centric study. Patients' inclusion will
 be performed in the "Internal medicine service of Cochin hospital, Assistance Publique -
 Hôpitaux de Paris (AP-HP)" during hospitalization and will be supervised by the pharmacology
 service of Cochin hospital.

 The evaluated drug is prednisone, used for routine care in auto-immune and other systemic
 inflammatory diseases. Prednisone will be administered according to the service usual
 practices, dosing will be determined according to the patient's disease. The study will not
 modify the prescription of the treatment. Blood tests will be performed at different
 intervals during each patient's normal biological monitoring of the treatment.

 Several tubes will be collected for the needs of the study at the time of each venipuncture
 (blood sample or peripheral venous catheter laying). The delay between drug intake and blood
 sampling will be attributed to routine care hazard, samples will be then realized on
 different occasions. No venous or arterial punction will be specifically planned for protocol
 purposes, GLUCOMAD's samples will be adapted to routine care blood samplings.

 1st visit : Patients recruiting phase Will occur during hospitalization. Its goal is to check
 for eligibility criteria.

 During this visit, the investigator will explain the patient the purpose of the study. The
 patient will receive an information notice and a consent form.

 Patient's data collection :

 -  Age

 -  Sex

 -  Pregnancy, menopause

 -  Personal history of kidney, liver or thyroid disease. Personal or familial history of
 adrenal pathology, impaired glucose tolerance, diabetes mellitus, gestational diabetes,
 high blood pressure, preeclampsia, hypertension in pregnancy, open angle glaucoma,
 cataract, osteoporosis/osteopenia, osteoporotic fracture, gastric ulcer, psychiatric
 disorder, dyslipidemia.

 -  Osteoporosis risk factors

 -  Blood pressure, body weight, height, and clinical exam results looking in particular for
 hepatocellular insufficiency, or uremic syndrome.

 -  Face photography at the beginning and the end of the study participation.

 Data collection about prednisone :

 -  Treatment indication

 -  Anterior corticotherapy, and optionally, anterior treatment duration, total dose taken
 up (as estimated by recovered orders from the patients pharmacy), and side effects of
 this previous treatment.

 -  Name of the chosen molecule (international nonproprietary name and commercial name),
 daily dosing (mg/Kg), treatment's start date.

 -  Adherence to the treatment, evaluated by the medication possession ratio (MPR42).

 -  Clinical symptoms of corticotherapy side effects Actual co-occuring treatments,

 -  Especially for medications interacting with P450 cytochrome, or P glycoprotein.
 Including the non proprietary name, treatment's start date, dosage, and optionally the
 results of plasma rates testing.

 -  Side effects treatments : anti hypertensive drugs, hypolipidemic drugs, potassium
 supplementation, oral antidiabetic drugs/insulin, psychotropic drugs.

 Blood tests Follow up

 -  During hospitalizations, routine care blood samples will be performed, on these
 occasions, blood will be collected in a dry tube for the study purposes.

 -  At the end of the attack phase, albumin, transcortin, HbA1c, and 8am cortisol will be
 assayed.

 -  Usual clinical and biological follow up results, including body weight and side effects
 monitoring, will be collected.

 -  Medication possession ratio assessment

 -  Co-occuring treatments Collection Sampling procedure, place of collection Blood samples
 necessary to the study will be stored in an anonymous way. Anonymity will be guaranteed
 all the study long.

 Storage location and conditions Samples for non pharmacological tests will be tested and
 destroyed. All the pharmacological samples will be stored during the study at -80°C in the
 pharmacology service of Cochin hospital where pharmacological analyses will be performed.

 Samples processing Molecules plasma assays will be performed in the drug dosing platform of
 clinical pharmacology service of Cochin hospital, AP-HP. Free and bound forms of prednisolone
 will be tested.

 Samples management Pharmacological samples will be stored at the end of the study for
 complementary studies.

 Statistical considerations Statistical analyses We propose to describe prednisone's
 pharmacokinetic in adults thanks to a population pharmacokinetic approach. This technique is
 specially adapted for populations affected by rare inflammatory diseases that are supported
 in internal medicine services. Indeed, it only requires a few measures in each patient and
 allows flexibility in data collection ; thus it enables us to assay concentrations on routine
 care samples. This method will allow us to describe an average subject pharmacokinetic and
 then to estimate interindividual variability in the population under prednisone treatment. We
 will the attempt to explain this variability according to covariates as age, bodyweight,
 size, liver or kidney insufficiency, or co-occurring treatments.

 Individual pharmacokinetic parameters will be estimated from this population model through a
 Bayesian estimation method. Potential associations between individual expositions (i.e.
 residual concentration, area under the curve, maximal concentration), and prednisone side
 effects will be studied.

 Pharmaco-statistical analysis will be made thanks to non linear mixed effects modelisation
 softwares (Monolix 4.2 or Nonmem 7) to calculate prednisone's pharmacokinetic parameters as
 well as inter-individual variability parameters on one hand and residual variability on the
 other hand (the latter including intra-individual variability and measurement error).

 The final model will be validated by a simulation technique. Briefly, 500 simulations of the
 final model will be generated from the original database. Then the 5th, 50th, and 95th
 percentiles of the simulated predictions will be compared to observations (the simulation
 median has to be close to the observation's median, and 90% of the observation must be
 between the 5th and 95th percentiles of simulations).
Inclusion Criteria:

 -  receiving Prednisone

 -  recruited in Service de Medecine Interne, Cochin hospital, Paris

 -  blood sample collected at least one time during his/her follow-up

 Exclusion Criteria:

 -  refusal

 -  hypersensitivity to prednisone or one of its excipients

 -  inability to take a blood sample