Population pharmacokinetic and pharmacodynamic modeling of acetazolamide in peritoneal dialysis patients and healthy volunteers.

PURPOSE: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of acetazolamide (ACTZ) in peritoneal dialysis patients, ACTZ 500 mg was administered intravenously to 7 healthy subjects (HV) and 8 peritoneal dialysis patients (CAPD). METHODS: Population PK/PD modeling was performed with ACTZ serum (total and unbound), urine and dialysate concentrations, intra-ocular pressure (IOP) and covariates. A multi-compartment PK model (accounting for non-linear protein binding) and an inhibitory Emax (maximal change in IOP) PD model were selected. RESULTS: As expected, renal clearance (which almost equals total body clearance) was severely decreased in CAPD (1.2 vs 80.3 L/h) and the elimination half-life of total ACTZ was prolonged (20.6 vs 3.4 hours). The protein binding was significantly altered with a mean free fraction 4.2% in HV and 8.6% in CAPD. Moreover protein binding of ACTZ was concentration dependent in both HV and CAPD. Despite a higher free fraction of ACTZ, the Emax was lower in CAPD: 4.4±1.4 vs 7.4±2.8 mmHg. CONCLUSION: Both PK and PD are significantly altered in dialysis patients.

The use of depot-medroxyprogesterone acetate in contraception and its potential impact on skeletal health.

BACKGROUND: In the fall of 2007, the controversy about the contraceptive use of depot-medroxyprogesterone acetate (DMPA) and its potential impact on skeletal health reached the media in the province of Quebec, Canada, thereby becoming a matter of concern for the lay public and physicians. In order to discuss this subject openly, the National Institute of Public Health of Quebec (INSPQ) organized a scientific meeting on February 15, 2008, with targeted physicians delegated by their medical associations in the fields of general practice, obstetrics and gynaecology, rheumatology, orthopaedic surgery, physiatry and endocrinology. STUDY DESIGN: Participants reviewed the scientific literature using the study classification method according to the level of evidence, reviewed published guidelines of medical societies and organizations on the subject and reached a consensus position. This manuscript presents a review of the literature and describes the consensus position of the targeted medical associations. RESULTS: The consensus position adopted by all the targeted medical associations determined that DMPA was a cost-effective contraceptive option that must be considered in the light of the clinical situation and preference of each woman. Candidates for injectable contraception should be informed that the use of DMPA is associated with a slight decrease in bone mineral density (BMD), which is largely, if not completely, reversible. There should not be an absolute limit to the length of time that the DMPA contraceptive is used, regardless of the woman's age. Monitoring BMD is not recommended among users of DMPA for contraceptive purposes. Finally, the consensus statement declared that, although supplements of calcium and vitamin D are beneficial for skeletal health for women in general, such supplementation should not be recommended solely based on a woman's use of DMPA. CONCLUSION: Given the scientific evidences, DMPA use remains a valid contraceptive option for women. Its potential impact on BMD must be balanced against the significant individual, familial and social consequences of unintended pregnancy.