Clinical drug-drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P-glycoprotein.

Ivacaftor is approved in the USA for the treatment of cystic fibrosis (CF) in patients with a G551D-CFTR mutation or one of eight other CFTR mutations. A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect of ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients. The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6. Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin.

Influence of psychosocial factors on adolescent compliance with oral contraceptives.

This paper prospectively tests the influence of a variety of sociomedical and psychosocial factors on compliance with oral contraceptives among adolescent females from a population at high risk for pregnancy. Fifty-six females aged 14-19 yr from a lower socioeconomic background received a battery of pretest measurements and were then given Ortho-Novum 1/35 combined with riboflavin during an initial visit and 1-, 2-, and 4-month follow-ups. Compliance was measured at each follow-up using a Guttman scale consisting of: (1) avoidance of pregnancy, (2) appointment adherence, (3) pill count, and (4) urinary fluorescence for riboflavin. Six factors were found to be significantly associated with noncompliance: (1) multiple sexual partners, (2) appointment being made by the adolescent, (3) low evaluation of personal health, (4) feelings of hopelessness, (5) worry about becoming pregnant, and (6) previous abortion. These findings suggest that certain indicators of sexual activity and social psychological status may help predict noncompliance in some adolescent females.

Pharmacokinetics of norethindrone in Indian Women.

Pharmacokinetics of norethindrone (NET) was evaluated in eleven women belonging to a low socio-economic group and in five womem belonging to the high socio-economic group after the administration of an oral dose of 0.35 mg NET minipill on an empty stomach. Blood samples were collected at different intervals of time over a period of 24 hours. Plasma NET was estimated by radioimmunoassay. In all women, peak levels of NET occurred within 1-2 hours and a semi-log plot of plasma NET levels showed a biexponential decline. The half-life of plasma NET clearance was relatively shorter in women of low socio-economic group with poor nutritional status as indicated by anthropometric indices, as compared to that in well nourished women of high socio-economic group. There was a significant positive correlation between weight/(height) 2x 100 index on the one hand and t1/2 (beta) on the other in all the women studied, thereby suggesting a role for nutritional status in the metabolic handling of NET.

PIP: A correlation between nutritional levels and norethindrone pharmacokinetics was evaluated in 11 women of low socioeconomic status (SES) and 5 women of high SES. An oral dose of .35 mg of norethindrone was administered on an empty stomach in mini-pill form. Radioimmunoassay was used to measure plasma norethindrone from blood samples collected at different intervals over 24 hours. Peak norethindrone levels occurred in all women within 1-2 hours, and a semilog plot of plasma norethindrone concentration showed a biexponential decline. Peak values ranged from 7.7-12.3 ng/ml and 4.7-l4.8 ng/ml in high SES and low SES, respectively. Plasma levels of norethindrone at 12 hours were very low in low SES and could not be detected in 8 women at 25 hours. In contrast was the finding that all 5 high SES subjects had more than detectable levels of drug throughout the experimental period. Anthropometric indexes showed the low SES group with poor nutritional status had shorter half-life clearances than the relatively well-nourished high SES group. There was also a significant correlation between weight/(height) sq. times 100 index on the one hand and the time l/2-beta on the other in all women studied, thereby suggesting a role for nutritional status in the metabolic handling of norethindrone.

Assessment of the specificity of norethisterone radioimmunoassays.

PIP: Specifities of 4 different norethisterone (Nor) antisera (coded A,B,C, and D) were evaluated and compared by cross-reaction studies to relate the antiserum specificity to the overall specificity of the radioimmunoassay (RIA), as established by plasma levels measured in women regularly taking the microdose of Nor (300 mcg/day). Using any of the 4 antisera, no significant deviation from parallelism were found among graded doses of authentic Nor and increasing volumes of plasma from women taking Nor for contraception. Cross-reaction studies preceded by chromatography to decrease plasma blanks are described, with each antiserum compared to the others for its efficacy in estimating plasma Nor values. It was concluded that 1) the significance of cross-reaction studies as well as that of a parallelism test for assessing overall specifity of the RIA is limited; 2) a single chromatography before RIA improves assay specificity but may not be sufficient to remove all interfering compounds; and 3) a comparison of direct and chromatographic procedures using several different antisera is useful for selection of the relatively most specific RIA procedure. These study results indicated that either antiserum C or D (preceded by chromatography) will yield better results than A or B.^ieng