Inter-individual Coefficients Of Variation Research Articles

Clinical pharmacokinetics of mycophenolate mofetil.

The pharmacokinetics of the immunosuppressant mycophenolate mofetil have been investigated in healthy volunteers and mainly in recipients of renal allografts. Following oral administration, mycophenolate mofetil was rapidly and completely absorbed, and underwent extensive presystemic de-esterification. Systemic plasma clearance of intravenous mycophenolate mofetil was around 10 L/min in healthy individuals, and plasma mycophenolate mofetil concentrations fell below the quantitation limit (0.4 mg/L) within 10 minutes of the cessation of infusion. Similar plasma mycophenolate mofetil concentrations were seen after intravenous administration in patients with severe renal or hepatic impairment, implying that the de-esterification process had not been substantially affected. Mycophenolic acid, the active immunosuppressant species, is glucuronidated to a stable phenolic glucuronide (MPAG) which is not pharmacologically active. Over 90% of the administered dose is eventually excreted in the urine, mostly as MPAG. The magnitude of the MPAG renal clearance indicates that active tubular secretion of MPAG must occur. At clinically relevant concentrations, mycophenolic acid and MPAG are about 97% and 82% bound to albumin, respectively. MPAG at high (but clinically realisable) concentrations reduced the plasma binding of mycophenolic acid. The mean maximum plasma mycophenolic acid concentration (Cmax) after a mycophenolate mofetil 1 g dose in healthy individuals was around 25 mg/L, occurred at 0.8 hours postdose, decayed with a mean apparent half-life (t1/2) of around 16 hours, and generated a mean total area under the plasma concentration-time curve (AUC infinity) of around 64 mg.h/L. Intra- and interindividual coefficients of variation for the AUC infinity of the drug were estimated to be 25% and 10%, respectively. Intravenous and oral administration of mycophenolate mofetil showed statistically equivalent MPA AUC infinity values in healthy individuals. Compared with mycophenolic acid, MPAG showed a roughly similar Cmax about 1 hour after mycophenolic acid Cmax, with a similar t1/2 and an AUC infinity about 5-fold larger than that for mycophenolic acid. Secondary mycophenolic acid peaks represent a significant enterohepatic cycling process. Since MPAG was the sole material excreted in bile, entrohepatic cycling must involve colonic bacterial deconjugation of MPAG. An oral cholestyramine interaction study showed that the mean contribution of entrohepatic cycling to the AUC infinity of mycophenolic acid was around 40% with a range of 10 to 60%. The pharmacokinetics of patients with renal transplants (after 3 months or more) compared with those of healthy individuals were similar after oral mycophenolate mofetil. Immediately post-transplant, the mean Cmax and AUC infinity of mycophenolic acid were 30 to 50% of those in the 3-month post-transplant patients. These parameters rose slowly over the 3-month interval. Slow metabolic changes, rather than poor absorption, seem responsible for this nonstationarity, since intravenous and oral administration of mycophenolate mofetil in the immediate post-transplant period generated comparable MPA AUC infinity values. Renal impairment had no major effect on the pharmacokinetic of mycophenolic acid after single doses of mycophenolate mofetil, but there was a progressive decrease in MPAG clearance as glomerular filtration rate (GFR) declined. Compared to individuals with a normal GFR, patients with severe renal impairment (GFR 1.5 L/h/1.73m2) showed 3-to 6-fold higher MPAG AUC values. In rental transplant recipients during acute renal impairment in the early post-transplant period, the plasma MPA concentrations were comparable to those in patients without renal failure, whereas plasma MPAG concentrations were 2- to 3-fold higher. Haemodialysis had no major effect on plasma mycophenolic acid or MPAG. Dosage adjustments appear to not be necessary either in renal impairment or during dialysis. (ABSTRACT TRUN

Superoxide dismutase, catalase and glutathione peroxidase activities in human blood: influence of sex, age and cigarette smoking.

To obtain reference ranges for each of the main antioxidant enzymes (AOE) and analyze the influence of sex, age, and cigarette smoking on AOE activity in human blood. We investigated superoxide dismutase (SOD), catalase (CAT), and seleno-dependent glutathione peroxidase (GSH-Px) activities in the whole blood from 103 healthy subjects, from 18-67 years old (51 males and 52 females). We found a large and highly significant interindividual variability in the activity of all the AOE studied (p < 0.001). The interindividual coefficients of variation were 13.5% for SOD, 21.0% for CAT, and 36.2% for GSH-Px, indicating that GSH-Px exhibits the highest interindividual variability. Females showed higher SOD (p < 0.001) and CAT (p < 0.001) activities but lower GSH-Px (p < 0.05) activity than males. We found a significant effect of age on SOD activity (p < 0.001), showing that in human blood it decreases with age and that this decrease is not linear, beginning at 28 years of age. We also observed a linear effect of age on GSH-Px activity indicating that the activity of this enzyme increases with age (p < 0.01). No effect of age on CAT activity was observed (p > 0.05). AOE activity in smokers was found not to be significantly different from that observed in non-smokers (p > 0.05) except in the case of CAT activity in females, which was found to be lower in smokers than in non-smokers (p < 0.05). In addition, we determined reference ranges for the activity of each antioxidant enzyme studied. Our results confirm that AOE activity in human blood exhibits a wide interindividual variability and suggest that this variability may be ascribed, at least in part, to the sex and age of the individuals. Moreover, our results suggest that cigarette smoking does not influence AOE activity in human blood. Accordingly, it is suggested that for clinical purposes it may be necessary to consider the sex and age of the subjects involved in the study.

Measurement of skin mechanics: A study of inter- and intra-individual variation using the Dermaflex A.

Skin mechanics may be affected by a number of dermatological and systemic conditions, and reliable quantification of skin distension may therefore be of considerable interest. This study was undertaken in order to assess the intra-and inter-individual variation of measurements of skin distensibil-ity when using Dermaflex A. Dermaflex is a suction device that measures the deformation of the skin surface within a 10- mm cup following application of given suction. Three levels of suction were studied on the flexural side of the forearm in 19 healthy volunteers. Increasing levels of suction produced significantly increasing skin distension (P<0.0001) with a significant non-linear trend (P=0.0310). Inter-individual variation (coefficient of variation range 15.43-27.88%) was significantly larger than intra-individual variation (coefficient of variation range 9.16-11.45%, P=0.0031) throughout the range of suction tested. There was no significant difference between the intra- and inter-individual coefficients of variation with different levels of suction. The results suggest that measurements of skin distensibility can be a useful method for objective determination of skin mechanics.

Day-to-day intraindividual reliability and interindividual differences in monoamines excretion

The urine of 44 normal men was collected during 2 nights to evaluate components of biological variation i.e., intraindividual day-to-day variability and interindividual variability in monoamines excretion. Monoamines presented important interindividual variability [interindividual coefficients of variation (%): dopamine 18.3, norepinephrine 66.7, epinephrine 85.3, normetanephrine 22.4, metanephrine 76.8, 3-methoxy-4-hydroxyphenylglycol (MHPG) 77.0, vanilmandelic acid (VMA) 64.3, homovanilic acid (HVA) 71.3, 5-hydroxyindolacetic acid (5-HIAA) 20.4]. The reliability of these amounts was high, with intraclass correlation coefficients ranging from 0.43 ( P < 0.001) for MHPG free form to 0.65 ( P < 10 −6) for dopamine and normetanephrine (intraindividual coefficients of variation (%): dopamine 8.5, norepinephrine 39.9, epinephrine 45.9, normetanephrine 10.3, metanephrine 46.3, MHPG 37.5, VMA 30.7, HVA 41.0, 5-HIAA 12.3).

Lack of relationship between systemic exposure for the component drug of the fluorouracil, epirubicin, and 4-hydroxycyclophosphamide regimen in breast cancer patients.

The aim of this study was to investigate the covariance between the pharmacokinetics of the three components of the FEC regimen, epirubicin (EPI), fluorouracil (5-FU), and the cyclophosphamide (CP) metabolite 4-hydroxycyclophosphamide (4-OHCP), in breast cancer patients. Data from 21 women were collected over a total of 35 cycles. 5-FU (300 to 600 mg/m2) and CP (300 to 600 mg/m2) were administered as bolus injections, whereas EPI (15 to 60 mg/m2) was administered either as a bolus injection or as an infusion. The pharmacokinetics of the component drugs were monitored using a limited sampling scheme. Population pharmacokinetic models for each of the three drugs were developed using the program NONMEM. The data for 5-FU were best described by a one-compartment model with nonlinear elimination, where the maximal rate of elimination (Vmax) and the concentration at which the elimination was half-maximal (Km) were 105 mg/L.h and 27 mg/L, respectively. EPI concentration-time profiles showed a triexponential decline, with a mean terminal half-life of 24 hours and a clearance (CL) of 59 L/h. The elimination of 4-OHCP was monoexponential, with a mean half-life of 7 hours. The interindividual coefficients of variation (CVs) in CL were 30%, 22%, and 41% for 5-FU, EPI, and 4-OHCP, respectively. The corresponding values for intrapatient course-to-course variability in CL were 11%, 8%, and 27%. No significant correlation in any of the pharmacokinetic parameters between the drugs was found. Individualization of dosing of the FEC regimen using therapeutic drug monitoring and attempts to find concentration-response relationships may be successful, but requires that the exposure of all three drugs is considered simultaneously.

Microscopic photometric quantification of stiffness and relaxation time of red blood cells in a flow chamber

The Microscopic Photometric Monolayer Technique provides a tool to measure red blood cell (RBC) stiffness (resistance to elongation) and relaxation time. It combines many of the advantages of flow channel studies of point-attached RBCs with the simplicity, sensitivity and accuracy of photometric light transmission measurement This technique allows the study of the effects of physicochemical factors on the elongation and relaxation time of the same cells within an average of four to five thousand cells adhered as a monolayer to glass. Further, the time course of physicochemical effects on cell membrane and wash-in/wash-out kinetics of interactions can be followed. An automated version of this technique was developed. A dense monolayer of point-attached RBCs was prepared at the bottom of a flow-chamber. A steady-state flow, with stepwise increases of flow rate, induced the RBC elongation. The light transmission perpendicular through the monolayer plane was measured photometrically. Photomicrographs compared with photometric results showed that the flow-induced bending and curvature change of RBC membrane was associated with the increase of light transmission. There was a linear correlation between the photometric index of elongation and the elongation taken from photomicrographs for shear stresses up to 0.75 Pa. A stiffness parameter, S (in Pa), was defined as the ratio of shear stress and elongation at a shear stress of 0.25 Pa. Following a sudden flow stoppage, the RBCs returned to their resting shape and the RBC relaxation time was measured. The stiffness-relaxation time product, V (in mPas), was calculated to provide an estimate of viscosity. Diamide treatment, known to stiffen RBCs, did result in dose-dependent decreases of elongation and relaxation time. With increasing temperature, the relaxation time decreased at a rate of −2.96 ms/K; the stiffness increased significantly at a rate of 0.0038 Pa/K, and the stiffness-relaxation time product decreased with −2.95 mPas/K, reflecting an inverse relationship between RBC viscosity and temperature. Using the automated version of this technique (Elias-c-) to test RBCs of 36 healthy subjects, we found the inter-individual coefficients of variation to be 8.6% for stiffness, 7.9% for relaxation time and 12.4% for stiffness-relaxation time product.

The assessment of biological variation components of copper, zinc, and selenium

Twelve healthy volunteers (4 women and 8 men aged 23 to 45 years) were assessed for biological variation in copper, zinc, and selenium indices. Blood was drawn from these individuals once a week for 12 weeks and then once a month for a further 3 months. Over 12 weeks the mean plasma concentrations of copper, zinc, and selenium (measured by atomic absorption spectrometry), were 16 ± 2.9, 14.1 ± 1.5, and 1.28 ± 0.13 μmol/L, respectively. The intraindividual and interindividual coefficients of variation (estimated using analysis of variance (ANOVA) techniques) were 11 and 14% (zinc), 8 and 19% (copper), and 12 and 14% (selenium), respectively. The analytical goal for imprecision was achieved for all three micronutrients, i.e., it was less than one-half of the measured intraindividual variation. The indices of individuality for all three elements indicated that an individual's results as reference values are more useful than population-based data. The critical difference for significance between serial results is relatively smaller for copper (23%) and zinc (30%) than that for selenium (35%). The monthly mean concentrations of the three micronutrients over 6 months demonstrated no seasonal pattern.

Cutaneous and subcutaneous blood flow rates in paraplegic humans investigated by 133Xenon wash‐out. Methodological considerations

In a methodological study including 14 paraplegics and seven normal controls cutaneous and subcutaneous blood flow rates were investigated by 133Xenon wash-out after atraumatic labelling. In paraplegics, areas suffering pressure sores were included. The method was found applicable for the authors' purposes. In seven paraplegics median (95% confidence limits) cutaneous blood flow was 5.2 (2.4-8.5) ml (100 g min)-1 and subcutaneous 4.3 (2.0-13.2) ml (100 g min)-1. This did not differ from normal controls. In seven paraplegics with ischial pressure sores a trend for increased cutaneous blood-flow rates from areas adjacent to sores was obvious (P = 0.06). During 70 degrees head-up tilt, elimination-rate constants were reduced by a factor of 0.54 (0.50-0.70). A proximal blockade or infiltration of the 133Xenon depots with lidocaine did not inhibit employment of the method. The proximal block did not alter the local blood flow rate, but infiltration increased it in both paraplegics and normal individuals. Intra- and interdepot coefficients of variation were about 11% and 40% respectively. Interindividual coefficients of variation varied between 25% and 46%.

Cobalamin and cobalamin-binding capacity in human milk

Information on variability of cobalamin and its binding protein concentrations in human milk is scarce. We investigated their relationship and longitudinal changes up to the third month of lactation, and their inter and intraindividual variability within the day, between breasts and within the feed in samples from nine healthy lactating women. Cobalamin and its binding protein, cobalophin, expressed as cobalamin-binding capacity, presented higher correlations in colostrum and transition milk (r=0.621 and 0.842, respectively) than in other periods of lactation (r<0.500). Cobalamin was significantly higher (p<0.01) in colostrum (mean, all subjects: 0.35 nmol/l) than in the third month of lactation (0.25 nmol/l), whereas cobalamin-binding capacity was significantly lower (p<0.01) in colostrum (29 nmol/l) than in the third month (43 nmol/l). However, the patterns of individual longitudinal variation were different among women. There was a high intraindividual diurnal variability, with coefficients of variation (CV) in different individuals ranging from 15 to 42% for cobalamin, and from 16 to 52% for the binding protein, reflecting the variations between breasts and between different moments of collection within a day. Interindividual CV for samples obtained under identical conditions ranged from 32% (colostrum, morning, left breast) to 85% (1st month, afternoon, right breast) for cobalamin, and from 20% (2nd month, morning, right breast) to 90% (1st month, evening, right breast) for cobalamin-binding capacity. Comparing the means of all subjects in each period of lactation there were no significant differences, or even trends, in cobalamin and its binding protein between breasts, fore and hindmilk, and morning, afternoon and evening samples. Therefore, a representative sample of breast milk for cobalamin analysis in population studies can be obtained within a day of a determined lactation period irrespective of the time of day, breast or moment within a feed.

The reproducibility and sensitivity of sural nerve morphometry in the assessment of diabetic peripheral polyneuropathy.

The nerve fibre loss, atrophy and injury of diabetic peripheral polyneuropathy and their responses to metabolic intervention have been studied by morphometric analysis of sural nerve biopsies. The magnitudes and sources of intra- and inter-individual variation in these morphometric measures have not been investigated previously in a systematic manner. Morphometric parameters of nerve fibre damage were measured in four separate fascicles from bilateral sural nerve specimens obtained post-mortem from 13 diabetic and 13 non-diabetic subjects. Intra- and inter-individual coefficients of variation were computed and compared to the magnitude of the differences between normal and diabetic subjects. Several morphometric variables emerged as highly sensitive and reproducible measures of nerve fibre damage suitable for clinical studies of diabetic peripheral polyneuropathy. These observations provide a rational basis for the design of future clinical trials employing morphometric end-points.

Variability in transepidermal water loss of the skin: evaluation of a method to assess susceptibility to contact dermatitis in epidemiological studies

Transepidermal water loss (TEWL) has been suggested to be a measure which can be used to identify subjects at risk for the development of contact dermatitis. Transepidermal water loss is high when the barrier function of the skin is impaired. It is assumed that subjects with a high TEWL have skin which is more permeable to substances causing contact dermatitis. The inter-individual and intra-individual variability of simultaneous TEWL measurements and TEWL measurements over a period of three weeks were estimated in healthy individuals. The intra-individual coefficient of variation (CV) of simultaneous measurements was 13.5%. The intra-individual coefficient of variation of the measurements on consecutive days was somewhat higher (15.1%). The intra-individual coefficients of variation were low compared to the inter-individual coefficients of variation. The results indicate that transepidermal water loss is a stable personal characteristic, which can be studied as a risk factor in epidemiologic studies on contact dermatitis.

Pharmacokinetics of three bioequivalent norethindrone/mestranol-50ug and three norethindrone/ethinyl estradiol-35ug oc formulations: Are “low-dose” pills really lower?

We have examined the pharmacokinetic parameters derived from the analysis of plasma ethinyl estradiol (EE) and norethindrone levels after administration of a single dose of three bioequivalent norethindrone-lmg/mestranol (ME)-50ug formulations (Ortho-Novum R 1 50 , Norinyl R 1 50 and Norcept-M R 1 50 ) and three norethindrone-lmg/ethinyl estradiol-35ug formulations (Ortho-Novum 1 35 R, Norinyl R 1 35 , Norcept-E R 1 35 ) in a randomized crossover design involving 24 women for the 35ug and 27 women for the 50ug agents. Differences between the AUC-EE of pairs from the same manufacturer (1 + 35 and 1 + 50) were not significantly different, indicating that 50ug of mestranol was equivalent to 35ug ethinyl estradiol with respect to this pharmacokinetic parameter. The C max values were also similar. Inter-individual coefficients of variation (C.V.) for the AUC-EE were 47% and 57% for the 1 + 35 and 1 + 50 agents, respectively. Intra-individual C.V.s were 41% and 42%, respectively. For norethindrone, the AUC was larger with the 1 + 50 formulations than with the 1 + 35 group (87.9 vs. 72.8 pg hr/ml). Additionally, the C max values were larger for the 1 50 group (17.7 vs. 14.0). Since the amount of norethindrone in the two dosage groups was the same, this difference in the pharmacokinetics between the 35ug EE and the 50ug ME formulations remains unexplained. The inter-individual C.V. averaged 56% for both dosage groups. The intra-individual C.V.s were 17% and 46% for the 1 + 35 and 1 + 50 groups, respectively. The large variation in blood levels of ethinyl estradiol and norethindrone between and within individuals may overshadow clinical differences attributable to differences in dosage.

Absorption and miscibility of regular porcine insulin after subcutaneous injection of insulin-treated diabetic patients.

The absorption and miscibility of subcutaneously injected 125I-regular porcine insulin was examined in 20 insulin-treated diabetic patients. The disappearance half-life (t1/2) was 2.1 +/- 0.8 h (SD) after injection of regular insulin (40 U/ml) and 2.3 +/- 0.7 h when mixed with porcine NPH insulin (NS). A significant inverse relation was demonstrated between insulin concentration and absorption, as t1/2 was 1.8 +/- 0.7 h (P less than 0.05) when using 20 U/ml. The interindividual coefficients of variation for absorption of regular insulin were 30.9-41.6% and independent of the presence of NPH insulin. The intrapatient variability, however, was much smaller, 14.5-23.6%.

Long-term variability in serum thyroglobulin and thyroid related hormones in healthy subjects.

From 5 young males and 5 young females blood was drawn under highly standardized conditions at 6 to 10 occasions during 4 months. The serum constituents thyroglobulin, thyroxine, triiodothyronine, T3-uptake test, TBG and TSH were determined, and four indices were calculated. The biological intra-individual coefficients of variation were below 0.14 for thyroglobulin, and the inter-individual coefficients for variation ranged from zero for T3-uptake test to 0.35 for thyroglobulin. All results were within the generally accepted reference ranges for normals. Within these ranges the calculations of indices for free thyroxine and triidothyronine according to T3-uptake test and TBG, did not significantly reduce the coefficients of variation for these serum constituents. Thyroglobulin concentrations did not correlate to any of the measured or calculated constituents. The knowledge of these intra- and inter-individual variations of serum thyroglobulin in healthy persons is of importance for the interpretation of variations found in patients.

Technical pitfalls in measurement of venous plasma NH3 concentration.

Measurement of venous plasma NH3 in normal subjects by the ion-exchange method of Forman [Clin. Chem. 10, 497 (1964)] in a hospital clinical laboratory gave a mean value of 640 mug/liter (range, 300-1320 mug/liter; intraassay, intra-individual, and inter-individual coefficients of variation, 8, 47, and 47%, respectively). The following conditions adversely affect the reproducibility of the test: pollution of laboratory atmosphere and glassware by NH3-containing detergents; smoking by patient or analyst; delay, turbulence, or use of heparin lock in venipuncture; delay or warming of plasma above degrees C before mixing it with resin; and delay in colorimetric analysis of resin eluate. When these sources of error were eliminated, the mean value for normals was reduced to 330 mug/liter, the range was narrowed to 220-470 mug/liter, and the above-mentioned CV's were 5, 16, and 17%, respectively. With the precautions cited, furthermore, the intra-assay and intra-individual CV's for fasting NH3 concentration in cirrhotic patients were similarly reduced. An NH3 tolerance test was done by administering a standard dose of NH4Cl to patients and measuring venous plasma NH3 at 0, 15, 30, 60, and 90 min; the NH3 tolerance was quantified from the area under the curve relating concentration to time (mug - min/liter). As measured in the clinical laboratory, NH3 tolerance of cirrhotic patients showed intra-assay and intra-individual CV's of 50 to 90%. When the tolerance tests were repeated in the same subjects with the laboratory precautions listed above, these CV's were reduced to 8-15%.

The influence of weight and of stature on the mechanical efficiency of men.

A study was made of the influence of two anthropometrical factors, weight and height, on the oxygen intake, and therefore on the gross mechanical efficiency, of a selected group of 16 men engaged in three tasks. Measurements of heart rate and oxygen intake were made at four levels of work rate in each of the tasks of shovelling, tramming and pedalling a bicycle ergometer. Intra- and inter-individual coefficients of variation were very similar, being between 3 and 8 per cent. Total coefficients of variation were between 5 and 10 per cent for most of the tasks. Evidence was presented that “skill” accounts for differences in mechanical efficiency between individuals in all tasks. In shovelling sand, neither weight nor height had a significant influence on the differences in oxygen consumption between individuals. It was concluded that in walking, cycling at moderate rates, and tramming at high rates, a light man is more mechanically efficient than a heavy man, and a tall man is more mechanically efficient than a short man. The higher heart rates of light individuals compared with heavy individuals when performing similar tasks is discussed in relation to differences in their respective maximum oxygen intakes.