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* From the Department of Medicine (Drs. Peloquin and Namdar and Mr. Singleton), National Jewish Medical and Research Center, Denver, CO; School of Pharmacy (Dr. Peloquin) and School of Medicine (Dr. Peloquin), University of Colorado Denver; and School of Pharmacy (Dr. Nix), University of Arizona, Tucson, AZ.
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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Design: Randomized, four-period crossover phase I study.
Subjects: Fourteen healthy male and female volunteers.
Interventions: Subjects ingested single doses of RIF, 600 mg, under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. They also received standard doses of isoniazid, pyrazinamide, and ethambutol.
Measurements
and main results: Serum was collected for 48 h and assayed
by high-pressure liquid chromatography. Data were analyzed using
noncompartmental methods and a compartmental analysis using
nonparametric expectation maximization. Both fasting conditions
produced similar results: a mean RIF maximal serum concentration (Cmax)
of 10.54 ± 3.18 µg/mL, the time at which it occurred (Tmax) of
2.42 ± 1.32 h, and the area under the curve from time zero to
infinity (AUC0–
) of 57.15 ± 13.41 µg ·
h/mL. These findings are similar to those reported previously. Antacids
did not alter these parameters (Cmax of 10.89 ± 5.22 µg/mL, Tmax
of 2.36 ± 1.28 h, and AUC0– of 58.37 ± 18.49
µg · h/mL). In contrast, the Food and Drug Administration
high-fat meal reduced RIF Cmax by 36% (7.27 ± 2.29 µg/mL), nearly
doubled Tmax (4.43 ± 1.09 h), but reduced AUC0– by
only 6% (55.20 ± 14.48 µg · h/mL).
Conclusions: These changes in Cmax, Tmax, and
AUC0– can be avoided by giving RIF on an empty stomach
whenever possible.
Key Words: antacids • bioavailability • food • Mycobacterium avium complex • Mycobacterium tuberculosis • pharmacokinetics • rifampin
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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We examined the pharmacokinetics of RIF in healthy volunteers under fasting conditions (two replicates), with food, and with an aluminum/magnesium hydroxide antacid. This study describes the serum concentrations and the pharmacokinetic behavior under optimal conditions, and can be used as benchmarks for comparison with samples obtained in other clinical settings.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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2 times
normal), the cardiovascular system (New York class I to IV heart
failure), or a hematocrit < 36% at screening. They also were
excluded if they had known GI diseases that might affect the absorption
of the drugs, known positive HIV serology, AIDS, or histories of
adverse reactions to INH, RIF, PZA, EMB, or related drugs. They also
were excluded if they weighed > 130% of ideal body weight, were
pregnant or nursing, or donated blood within 30 days prior to
study.7
The subjects agreed to refrain from the use of
other prescription or nonprescription drugs (including vitamins) and
alcohol during the entire study period. Women who were taking oral
contraceptives at the start of the study were allowed to continue
taking these during the study. They were required to agree to use
additional contraceptive methods during the study period and for a week
after the last dose of RIF. At the conclusion of the study, each
subject underwent a brief physical examination and had blood drawn for
serum chemistry and hematology study, and female subjects had repeat
pregnancy testing.
Experimental Design
Sixteen subjects were randomized in four blocks of four
subjects. The four treatments were fasting conditions (twice, to
determine the intrasubject variability), with a high-fat meal, and with
aluminum-magnesium antacid. They were housed at the study center from
10 h before to 24 h after dosing, and returned for the 36-h
and 48-h collections. After receiving a light snack prior to 11
PM, they fasted overnight. For three of the treatments,
they continued to fast for 4 h after the dose. On one of these
three fasting occasions, they also took 30 mL of aluminum/magnesium
hydroxide (Mylanta) 9 h before dosing, at the time of dose, after
meals, and at bedtime postdose. For the fourth treatment, they consumed
the standard Food and Drug Administration high-fat breakfast beginning
0.25 h before dosing. This meal consisted of 8 oz of whole milk,
two scrambled eggs, two strips of bacon, two slices of toast with two
butter pads, and one hash brown potato patty. The meal provided an
estimated 53 g of carbohydrate, 33 g of protein, and 51
g of fat, for 792 Kcal, 57% as fat. Subjects received single oral
doses of RIF, 600 mg. They also received 300 mg INH, 30 mg/kg PZA
(median, 2,386 mg), and 25 mg/kg EMB (median, 1,950 mg). Doses for all
treatment periods were based on the subjects' prestudy weights. The
subjects were allowed to ingest water ad libitum after the
doses were given, and identical, nutritionally balanced meals were
provided to all subjects during the remainder of the study period.
There was a 14-day washout between each study period.
Sample Collection
A 20-gauge angiocatheter was inserted into a forearm vein for
the collection of blood samples, and was maintained patent using a
dilute heparin solution (10 to 15 U/mL). Two milliliters of blood was
withdrawn and discarded prior to collecting each blood sample (12 mL)
into plain red-top vacuum tubes. Serial blood samples for serum drug
concentration analyses were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2,
2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 h after the doses.
Samples were allowed to clot for 30 min, then centrifuged at 2,500 to
3,000g for 10 min. Serum samples were then harvested and
frozen at 
-70°C for 5 months until assay. We have determined
previously that RIF is stable in human serum for > 24 h at room
temperature, and it is stable for periods of > 1 year when frozen at
-70°C.8
Urine samples were collected within 30 min of dosing (baseline). Subsequently, all urine was collected from 0 to 12 h and from 12 to 24 h. Subjects were asked to void near the end of each collection period. Samples were kept refrigerated during the period of collection. The total volume was measured at the end of the collection period, and 10-mL aliquots from each collection were frozen at -70°C until assay.
Sample Analysis
All high-pressure liquid chromatography (HPLC) assays were
performed using a validated HPLC assay on a pump (Waters 510 pump;
Milford, MA) and model 680 gradient controller with a solvent select
valve, a model 8875 fixed-volume autosampler (Spectra Physics; San
Jose, CA), a model 486 ultraviolet detector (Waters), a computer
(Macintosh IIci; Apple Computers Inc; Cupertino, CA), and an HPLC data
management system (Rainin Dynamax; Woburn, MA). The six-point standard
curves for the RIF ranged from 0.5 to 50 µg/mL, with linearity
extending well above this range. The absolute recovery of RIF from
serum was 95.5%, as determined by comparing peak height counts across
four serum curves to an unextracted solvent curve. The within-day
precision (percent coefficient of variation [CV]) of
validation quality control (QC) samples was 2.4 to 4.6%, and the
overall validation precision was 6.3 to 7.1%. QC sample concentrations
were 26, 8, and 3 µg/mL. The urine method standard curves for RIF
ranged from 0.5 to 200 µg/mL, with similar recovery and
reproducibility. The assay error pattern was determined from serum
standard curve samples assayed over the course of the validation. A
second-order polynomial was fit to the plot of the QC standard
deviations (Y) vs their means (X). The assay error pattern used for the
subsequent pharmacokinetic analysis was
y = 0.0350 + 0.0046x - 0.0001x2,
R2 = 0.992.9
Pharmacokinetic Analysis
Serum concentrations below the quantification lower limit were
treated as zeros in averaging the concentrations at a given collection
time. Data were initially analyzed using noncompartmental methods. The
observed maximal serum concentration (Cmax) and the time at which it
occurred (Tmax) were determined for each subject by inspection of the
serum concentration-vs-time graphs. The area under the serum
concentration-vs-time curve (AUC) from time zero to the time of the
last quantifiable concentration (AUC0–t*) was
determined by the linear trapezoidal rule. The last quantifiable
concentration was denoted C*. The AUC from time zero to infinity
(AUC0–) was determined as
AUC0–t* + C*/K, with the elimination rate
constant (K) determined using nonparametric expectation maximization
(NPEM) (see below). The potential for accumulation of RIF was evaluated
using the principle of superposition.10
The accumulation
of RIF with eight daily doses was simulated using the median serum
concentration data from 0 to 24 h (first fasting treatment), and
extrapolated from 24 h to day 8 using the median NPEM K.
Population pharmacokinetic models were made using software (NPEM2,
USC*PACK v.10.6; Laboratory of Applied Pharmacokinetics, USC; Los
Angeles, CA).11
F, the fraction of the dose absorbed, was
arbitrarily fixed at 1. Based on our previous work with RIF, and based
on the log-linear decline of serum concentrations post Cmax, a
one-compartment open model with first-order absorption and elimination
was used, weighted by the inverse assay variance error pattern
described above. NPEM obtained the joint probability density functions
of the final pharmacokinetic parameters. Three parameters were fit in
the initial analyses (absorption rate constant [ka], volume of
distribution [V], and clearance [C]). The loglikelihood criterion
was used to determine the best fit among candidate models. A second
analysis was done using ka, V, and K for fasting 1 state to verify the
results and to address problems that may arise with one set of
parameters but not the other, such as the "flip-flop" problem of
structural identifiability. The analyses were refined by restricting
the initial estimates of V to 0.4 L/kg. In addition, individual
subject Bayesian posterior parameter joint densities were estimated
starting from the population parameter joint density, and continuing to
analyze each subject's individual data to obtain the individual
parameter joint densities (post hoc analysis). These values
allow for the calculation of rate constants and half-lives across all
subjects. The absorption and elimination t1/2's were calculated as
ln(2)/ka and ln(2)/K, respectively.
D-optimal sampling time analysis was performed using software (ADAPT II) and the NPEM2 parameter estimates.12 The assay error pattern described above was used. Sampling times were analyzed using the parameters ka, V, and K over the period 0.5 to 24.0 h, with various initial sampling times and sampling time constraints. A two-sample strategy (achieved by fixing ka and fitting only V and K) and a three-sample strategy (achieved by fitting all three parameters) were tested. In addition, an analysis of Cmax was performed over the period 0.5 to 4.0 h, calculating the maximum, median, and minimum percentage for the measured concentration divided by Cmax.
Creatinine clearance (ClCr) was calculated by the method of Cockroft and Gault.13 The amount of RIF recovered in the urine was calculated as the measured volume of urine multiplied by the corresponding RIF concentration. Total recovery (mg) was calculated as the sum of the recoveries from the collection periods 0 to 12 h and 12 to 24 h, and the percent dose recovered was calculated as total recovery divided by dose multiplied by 100%. Renal clearance (Clr) was calculated as total recovery divided by AUC0–24.
Statistical Analysis
Data analysis was performed using software (JMP version 3.1.6;
SAS Institute; Cary, NC), with supplemental analyses done with other
software (Excel version 4.0; Microsoft; Seattle, WA). Frequency
distributions (JMP) included plots of the data, distribution curves to
test for normality, parametric and nonparametric measures of central
tendency and dispersion, as well as the Shapiro-Wilk W test for
normality. Means are reported ± the SD. The percent CV was
calculated as (SD/mean) multiplied by 100%. Differences among the
treatment groups were determined using an analysis of variance (ANOVA)
model that tested differences based on period, treatment, sequence, and
subject (sequence). Pairwise differences across the four treatments
were evaluated using individual linear contrasts. Bioequivalence
criteria were tested according to the 1992 Food and Drug Administration
guidelines.14
Cmax and AUC0– were log
transformation, and were analyzed using the ANOVA model described
above. Mean estimates and SEs were obtained from the linear contrasts,
and these were used to calculate the geometric means and the lower and
upper 90% confidence limits. Comparison treatments were considered
bioequivalent to the reference treatment (fasting treatment 2) if the
comparison parameter 90% lower limit was 80% and the upper limit
was 125%.
Correlation analysis (JMP) was performed across the subject and outcome
variables using nonparametric techniques (Spearman rho). The dependence
of outcome variables (the pharmacokinetic parameters) on subject
characteristics (demographic data such as age, weight, ClCr, etc) was
determined using Y by X analyses, one parameter at a time (JMP).
Subsequently, models with multiple X variables were constructed using
forward addition and backward deletion. Differences between groups
(JMP) were determined using the analysis of log likelihood with the
Pearson 
2 statistic (contingency tables), Student's
t test, or ANOVA (three or more groups) of normally
distributed data (one-way layouts and linear regression), the Wilcoxon
or the Kruskal-Wallis tests (rank sums) for nonnormally distributed
data (one-way layouts), and the whole-model test table with
2 statistic (logistic regression). Differences between
groups or correlations between parameters and covariates were
considered statistically significant at p < 0.05.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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The absorption characteristics for RIF with the four treatments are
described in Table 1
,
and the corresponding mean RIF serum concentration-vs-time profiles
across the 14 subjects are shown in Figure 1
.
Under fasting conditions, variability in absorption of RIF was small
(Table 1
) and the individual results quite reproducible (Fig 2
).
The mean RIF Cmax was unaffected by antacids, but significantly
decreased by food (-36%) (p < 0.0017). The mean RIF Tmax was
unaffected by antacids, while substantially increased by food (+103%)
(p < 0.0001). The Tmax was 3 h for 12 of 14 subjects when fed,
compared with 2 subjects in the other groups. The mean RIF
AUC0– was unaffected by antacids, and showed a small
reduction with food (-6%) (p = 0.76). Using the bioequivalence
criteria, food reduced the Cmax beyond the lower bounds (90%
confidence interval [CI], 55.8 to 78.2%), but not the
AUC0– (90% CI, 83.5 to 104.4%); and antacids did not
significantly affect the Cmax (90% CI, 80.3 to 112.5%) or
AUC0– (90% CI, 87.7 to 109.6%).
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During the analysis of the first fasting, fed, and antacid treatments, the NPEM program assigned very low volumes of distribution to the low absorbers, specifically those patients who had large C1 values. To overcome this problem, the data were reanalyzed while restricting the lower range of V to 0.4 L/kg. This value was the lowest within the post hoc NPEM2 individual parameter estimates for smooth absorbers, and was consistent with the lowest values seen in a previous study.5 The problem of very small values for V was not encountered with the second fasting data set. Reanalysis of the second fasting data set while restricting the lower range of V to 0.4 L/kg produced little change in the parameter estimates.
Table 2 shows the parameter estimates for RIF following the 600-mg dose as calculated using post hoc NPEM2 individual parameter estimates (second fasting treatment, unrestricted V). The various parameter estimates were not significantly different across the fasting and antacid treatments. However, the V was larger (p = 0.0015) and K was longer (p = 0.0017) in the fed group.
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and Cmax were lower in heavier
patients (r = -0.5396, p = 0.0464 and r = -0.4846,
p = 0.0791), respectively. The RIF excretion 0 to 12 h did not
correlate with RIF Cl or RIF Clr. In addition, there was no correlation
between CrCl and either RIF Cl or RIF Clr. |
Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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RIF was well absorbed and most Tmax values were near 2 h. The D-optimal sampling times for the two-sample strategy were 3.1 h, and as late as 14.9 h after the dose. This strategy assumes a low level of detection for the assay. Samples drawn from 1 h to 6 h postdose approached Cmax, although the 2- to 3-h samples were closest overall. The individual serum concentration-vs-time graphs displayed both the smooth and the low accumulation patterns. Under fasting conditions, variability across our 14 subjects was small and values were quite reproducible between the two fasting treatments for nearly all subjects.
Antacids did not effect the absorption of RIF. Therefore, antacids could be taken near the time of RIF dosing, provided that concurrent medications are not affected by the antacids. Based on our MEDLINE search, the effects of antacids on the absorption of RIF have not been described previously. We did find that the histamine-2 antagonist ranitidine has been shown not to effect RIF absorption.15
The high-fat meal had significant effects on the RIF, reducing Cmax
(-36%) and increasing Tmax (+103%). Food affected
AUC0– to a lesser extent (-6%). These results are
similar to those demonstrated by Siegler et al,16
who
studied 17 patients with active pulmonary tuberculosis; blood was
collected at baseline and five time points over 12 h postdose.
They showed a 25% reduction in Cmax, 100% increase in Tmax, and 23%
reduction in AUC when RIF was administered with a high-fat
meal.16
Zent and Smith17
administered RIF to
27 patients with active tuberculosis, and blood was collected at
baseline and 12 time points over 8 h, plus a 24-h postdose. When
RIF was given with a carbohydrate meal, a 15% reduction in Cmax, 19%
increase in Tmax, and 4% reduction in AUC were shown. In contrast,
when RIF was administered with a high-fat meal, these authors showed no
significant effect of RIF's Cmax, Tmax, and AUC.17
Polasa and Krishnaswamy18 studied six healthy men, dosing them with 10 mg/kg of RIF. Blood was collected at seven time points over 8 h postdose. A wheat-based breakfast consisting of 565 calories, including 9 g protein, 109 g carbohydrate, and 11 g fat was administered on one of two occasions. Compared with the fasting treatment, food reduced the mean Cmax by 30%, doubled the Tmax to 4 h, and reduced the AUC by 26%. Finally, Hagelund et al19 studied six patients with tuberculosis, in addition to six gastrectomized patients, collecting blood at 1, 3, 5, and 7 h postdose. They compared fasting conditions with a breakfast of bread with butter and marmalade, meat, cheese, one egg, and coffee or tea with milk.19 This meal delayed absorption, but showed only minor effects on Cmax and AUC in the nongastrectomized patients. Those with a history of GI surgery showed modest effects from food, but significant intersubject variability in RIF absorption, regardless of fed or fasting condition. The above articles show that RIF absorption can be affected by various types of meals. The precise content of each meal differed from study to study. It is possible that the specific foods consumed, as much as their content of carbohydrate, protein, or fat, played some role in the changes seen.
Narang et al20 studied the rifamycin derivative rifabutin, and showed that food had less of an effect on the Cmax (-17%) than we have shown for rifampin's Cmax (-36%). Their study also showed effects of food on the Tmax (+80%) and AUC (-5%) of rifabutin similar to our results for rifampin. Another rifamycin derivative, rifapentine, actually shows improved absorption with food. Owens et al21 demonstrated that food increased rifapentine's Cmax 50%, increased the Tmax by only 11%, and increased the AUC by 46%.
The correlations of Cmax and Tmax with age were relatively weak, although older subjects were significantly more likely to be smooth absorbers. The apparent difference between smooth and low absorbers is due, in part, to the blood sampling schedule. Such differences may not have been apparent with more frequent early blood samples. The negative correlation between weight and both the RIF AUC and the Cmax suggests that RIF should be dosed on a milligram per kilogram basis to avoid underdosing large patients.
The NPEM2 analysis produced parameter estimates consistent with those from our previous investigation.5 RIF displayed median values for K and t1/2 values similar to those from the previous study. The median values for V and Cl from this study were slightly larger. The reasons for these differences were not apparent, other than a different set of subjects were studied.
RIF is cleared predominantly through nonrenal mechanisms, with only 10% of the drug reported to be cleared unchanged in the urine over 24 h.20 We have reproduced those findings. RIF is converted to 25-desacetylrifampin and other, less abundant metabolites, which are subsequently cleared through nonrenal and, to a lesser extent, renal mechanisms. 25-desacetylrifampin displays microbiological activity approaching that of RIF, while displaying serum concentrations approximately 10% of those for RIF. We did not assay the metabolite in our study.
RIF has good activity against Mycobacterium tuberculosis and modest activity against Mycobacterium avium. Using radiometric techniques, Heifets22 determined the minimal inhibitory concentration (MIC) of RIF to be 0.25 µg/mL against M tuberculosis, and 4 µg/mL against M avium. Against an isolate of M tuberculosis with an MIC of 0.25 µg/mL, the RIF Cmax: MIC ratio is 42:1, and serum concentrations would remain above MIC for about 15 h. In contrast, against an isolate of M avium with an MIC of 4 µg/mL, the RIF Cmax: MIC ratio is < 3:1, and serum concentrations would remain above MIC for about 4.5 h. This analysis is consistent with RIF's superior activity against M tuberculosis compared with M avium.
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Conclusions |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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Footnotes |
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This study was supported, in part, by NIH grant 1 RO1 AI37845.
Correspondence to: Charles A. Peloquin, PharmD, Director, Infectious Disease Pharmacokinetics Laboratory, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80206; e-mail: peloquinc@njc.org
Abbreviations: ANOVA = analysis of
variance; AUC = area under the curve; AUC0– = area
under curve from time zero to infinity; C = clearance;
CI = confidence interval; ClCr = creatine clearance; Clr = renal
clearance; Cmax = maximal serum concentration; CV = coefficient of
variation; EMB = ethambutol; HPLC = high-pressure liquid
chromatography; INH = isoniazid; K = elimination rate constant;
ka = absorption rate constant; MIC = minimal inhibitory
concentration; NPEM = nonparametric expectation maximization;
PZA = pyrazinamide; QC = quality control; RIF = rifampin;
Tmax = time at which maximal serum concentration occurred;
V = volume of distribution
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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