Risedronate Pharmacokinetics and Intra- and Inter-Subject Variability Upon Single-Dose Intravenous and Oral Administration

Purpose. To determine the pharmacokinetics and absolute bioavailability of risedronate after single-dose oral administration of 30 mg risedronate as a tablet and an aqueous solution, and 0.3 mg risedronate as an intravenous infusion. Methods. This study was a randomized, three-treatment, four-period, partial replicate crossover study involving 33 healthy volunteers. Treatments were administered 7 weeks apart, and the third treatment was repeated during the fourth period. Serum and urine were collected over 72 hours and 672 hours, respectively. Results. Following intravenous administration, renal clearance accounted for 87% of total clearance, with 65% of the dose excreted within 24 hours and 85% of the dose excreted within four weeks. The absolute bioavailability was approximately 0.62% after both oral formulations, and the relative bioavailability of the tablet compared with the oral solution was 104%. The rate and extent of absorption from the two formulations were bioequivalent based on the range proposed for highly variable drugs. Intrasubject variability following oral administration was 50-80%, and was primarily associated with absorption. Conclusion. The majority of the total clearance after intravenous administration of risedronate was renal clearance, indicating that only a small percentage of a systemic dose is potentially incorporated, or cleared, into bone. The absolute bioavailability of orally administered risedronate is 0.6%, and is independent of formulation. Variability in the pharmacokinetics following oral administration is primarily associated with intrasubject variability in absorption.     

Influence of Gastrointestinal Site of Drug Delivery on the Absorption Characteristics of Ranitidine

The absorption characteristics of ranitidine after delivery to three locations in the gastrointestinal tract were compared in an open-label study of eight healthy males. Subjects received ranitidine HCl (150 mg) for injection via a nasoenteric tube directly into their stomach, jejunum, or cecum sequentially in three separate periods (24 hr apart). Plasma samples were collected at periodic time intervals for 12 hr following each dosing and analyzed for ranitidine concentration by high-pressure liquid chromatography. Mean concentrations following cecal dosing were lower (P < 0.05) than concentrations following gastric or jejunal dosing at each sampling time except baseline. Mean concentrations following gastric and jejunal dosing were similar except at 2 hr (gastric > jejunal). Mean pharmacokinetic parameters for cecal administration were different (P < 0.05) from either the gastric or the jejunal periods with the exception of T_max. There was no difference in any pharmacokinetic parameter after gastric or jejunal dosing. The relative bioavailability after cecal administration was less than 15% of that observed after administration into the stomach or jejunum. Additionally, Wagner-Nelson analysis indicated that the rate of ranitidine absorption was much slower following cecal administration than after gastric or jejunal dosing. Two plasma concentration peaks were observed in three of eight subjects after gastric dosing, in eight of eight subjects after jejunal dosing, and in zero of eight subjects after cecal dosing. These data demonstrate that the absorption profile of ranitidine is equivalent, in extent and duration, after delivery to the stomach or jejunum, while absorption from the cecum is significantly less. In addition, the two plasma concentration peaks commonly seen with ranitidine administration are not secondary to variations in gastric emptying as has been hypothesized.     

Sumatriptan Absorption from Different Regions of the Human Gastrointestinal Tract

Sumatriptan exhibits low oral bioavailability partly due to presystemic metabolism, which may vary with regional differences in metabolic activity throughout the gastrointestinal tract. This study evaluated sumatriptan absorption in humans after administration orally and by oroenteric tube into the jejunum and cecum. Because the site of cecal administration varied, pharmacokinetic parameters for sumatriptan and its major metabolite were compared statistically only after oral and jejunal administration. One-half of the oral dose was recovered in the urine as parent (3%) and metabolite (46%). Sumatriptan was absorbed throughout the gastrointestinal tract; absorption was similar after oral and jejunal administration, and less after cecal administration. The metabolite AUC and the AUC ratio (metabolite/parent) were significantly lower after jejunal compared to oral administration; the AUC ratio was two-fold lower after cecal administration. Results suggest that presystemic metabolism of sumatriptan varies throughout the gastrointestinal tract and/or regional differences exist in the absorption of metabolite formed within the gastrointestinal tract.     

The Pharmacokinetics and Absorption of Recombinant Human Relaxin in Nonpregnant Rabbits and Rhesus Monkeys After Intravenous and Intravaginal Administration

Recombinant human relaxin (rhRlx) is being developed as a potential cervical ripening agent to be applied intravaginally or intracervically prior to parturition. The pharmacokinetics and absorption of rhRlx were determined in nonpregnant female rabbits and rhesus monkeys after intravenous bolus (iv) and intravaginal administration of 0.1 mg/kg; additionally, rabbits were dosed with 0.5 mg/kg intravaginally. In rabbits (n = 6), mean (±SD) peak concentrations following iv bolus administration were 1554 ± 296 ng/mL. The weight-normalized clearance (CL/W) was 5.9 ± 0.4 mL/min/kg, initial volume of distribution (V ₁/W) was 57 ± 9 mL/kg, and volume of distribution at steady state (V _SS/W), assuming central compartment elimination, was 240 ± 20 mL/kg. V _ss/W could be as large as 2000 ± 400 mL/kg without this assumption. The estimated amounts of rhRlx absorbed in rabbits following intravaginal administration of 0.1 and 0.5 mg/kg (n = 5/dose) were 3.1 ± 1.4 and 0.7 ± 0.3%, respectively; peak concentrations were 600 ± 297 and 1066 ± 584 pg/mL, respectively. In rhesus monkeys (n = 5) after iv administration, peak concentrations were 971 ± 277 ng/mL; CL/W was 4.1 ± 0.6 mL/ min/kg, V ₁/W was 78 ± 25 mL/kg, and V _ss/W, assuming central compartment elimination, was 690 ± 220 mL/kg. The upper limit for V _ss/W was 1600 ± 200 mL/kg when no assumptions were made regarding site (compartment) of elimination. After intravaginal administration (n = 6), two monkeys had undetectable rhRlx concentrations throughout the 48-hr sampling interval; one monkey had only one sample containing measurable rhRlx (51 pg/mL) at 24 hr; and three monkeys absorbed <2% of the 0.1 mg/kg dose. Peak concentrations in these three animals ranged from 64 to 1475 pg/mL. The absorption of rhRlx was low and variable in both species, and similar results have been observed in women.     

Absorption and Presystemic Metabolism of Nefazodone Administered at Different Regions in the Gastrointestinal Tract of Humans

Purpose. The absorption and disposition of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and triazole dione (dione) were assessed in 10 healthy subjects following infusion of NEF solution into the proximal and distal regions of the intestine vs administration of NEF solution orally by mouth. Methods. NEF HC1 (400 mg) was infused over 5 hours into the proximal or distal intestine through a nasogastric tube, or orally ingested in 10 divided doses over 4.5 hours. The three treatments in the three-period crossover design were separated by one week. Results. The bioavailability of NEF, based on AUC(INF), from proximal and distal regions relative to that from oral administration was 97% and 106%, respectively. NEF was absorbed equally well from all three treatments with median Tmax of 5.0 hours which coincided with the duration of infusion. Mean Cmax of NEF was not different between proximal and oral administrations, however, mean Cmax after distal instillation was 40% lower than that after oral administration. Exposure to HO-NEF, mCPP and dione, following proximal instillation was also comparable to that after oral administration. AUC(INF) of HO-NEF and dione was significantly lower after distal instillation compared to that after oral administration but AUC(INF) of mCPP was not. Cmax of all metabolites was significantly lower after distal administration in comparison to oral treatment. Terminal half-life for NEF, HO-NEF and mCPP after distal administration was longer than the other two treatments. Conclusions. NEF is absorbed throughout the length of the gastrointestinal tract which supports the development of an extended-release formulation of NEF. The exposure to the metabolites (relative to NEF) was lower from the distal intestinal site compared to the proximal and oral site which may be explained by a reduced first pass of NEF by the cytochrome P450 3A4 in the distal intestine.     

Gastrointestinal Drug Absorption: Is It Time to Consider Heterogeneity as Well as Homogeneity?

The current analysis of gastrointestinal absorption phenomena relies on the concept of homogeneity. However, drug dissolution, transit and uptake in the gastrointestinal tract are heterogeneous processes since they take place at interfaces of different phases under variable stirring conditions. Recent advances in physics and chemistry demonstrate that the geometry of the environment is of major importance for the treatment of heterogeneous processes. In this context, the heterogeneous character of in vivo drug dissolution, transit and uptake is discussed in terms of fractal concepts. Based on this analysis, drugs are classified in accordance with their gastrointestinal absorption characteristics into two broad categories i.e. homogeneous and heterogeneous. The former category includes drugs with satisfactory solubility and permeability which ensure the validity of the homogeneous hypothesis. Drugs with low solubility and permeability are termed heterogeneous since they traverse the entire gastrointestinal tract and therefore are more likely to exhibit heterogeneous dissolution, transit and uptake. The high variability of whole bowel transit and the unpredictability of conventional dissolution tests for heterogeneous drugs are interpreted on the basis of the fractal nature of these processes underin vivoconditions. The implications associated with the use of strict statistical criteria in bioequivalence studies for heterogeneous drugs are also pointed out.     

MDR1 Genotype-Related Duodenal Absorption Rate of Digoxin in Healthy Japanese Subjects

Purpose. Recent clinical studies suggest the importance of the MDR1 genotype at position 3435 (C3435T) in terms of pharmacokinetics, but there is still no consensus in reports on the relationship between the genotype and plasma/serum concentration-time profiles of drugs after conventional oral administration. This study was performed to elucidate the effects of C3435T on the rate of duodenal absorption of digoxin in healthy Japanese subjects. Methods. Digoxin solution was sprinkled directly over the surface of the duodenum using an endoscope, and its absorption rate was evaluated by serial monitoring of the serum concentration and by analysis of its initial 15-min increasing phase. Results. The duodenal absorption rates of digoxin were 911 ± 91 ng/min and 506 ± 76 ng/min for C/C and T/T, respectively (±SE, p = 0.007). Conclusions. The C3435T mutation of the MDR1 gene is associated with suppression of duodenal absorption of digoxin.     

The effect of dosing regimen on the pharmacokinetics of risedronate

AIMS: To examine the effect of timing of a risedronate dose relative to food intake on the rate and extent of risedronate absorption following single-dose, oral administration to healthy male and female volunteers. METHODS: A single-dose, randomized, parallel study design was conducted with volunteers assigned to four treatment groups (31 or 32 subjects per group, 127 subjects total). Each subject was orally administered 30 mg risedronate. Group 1 was fasted for 10 h prior to and 4 h after dosing (fasted group); Groups 2 and 3 were fasted for 10 h and were dosed 1 and 0.5 h, respectively, before a high-fat breakfast; and Group 4 was dosed 2 h after a standard dinner. Blood and urine samples were collected for 168 h after dosing. Pharmacokinetic parameters were estimated by simultaneous analysis of risedronate serum concentration and urinary excretion rate-time data. RESULTS: Extent of risedronate absorption (AUC and Ae ) was comparable (P=0.4) in subjects dosed 2 h after dinner and 0.5 h before breakfast; however, a significantly greater extent of absorption occurred when risedronate was given 1 or 4 h prior to a meal (1.4- to 2.3-fold greater). Administration 0.5, 1, or 4 h prior to a meal resulted in a significantly greater rate of absorption (Cmax 2.8-, 3.5-, and 4.1-fold greater, respectively) when compared with 2 h after dinner. CONCLUSIONS: The comparable extent of risedronate absorption when administered either 0.5-1 h before breakfast or 2 h after an evening meal support previous clinical studies where risedronate was found to have similar effectiveness using these dosing regimens. This flexibility in the timing of risedronate administration may provide patients an alternative means to achieve the desired efficacy while maintaining their normal daily routine.     

Regional Gastrointestinal Absorption of Ranitidine in the Rat

Purpose. Ranitidine absorption from isolated segments of rat small intestine (duodenum, midgut, and terminal ileum) was investigated to examine the influence of pH and 50% bile, and to determine if ranitidine is absorbed preferentially from a specific region. Methods. Ranitidine (50 mg/kg) was administered into each segment in pH 5 or pH 7 buffer, or in 50% bile. Venous blood was collected at various times for 40 min from the right jugular vein. Results. When ranitidine was administered in pH 7 buffer or in 50% bile, C _max and AUC_0–40 were significantly greater after administration into the terminal ileum compared to the duodenum and midgut. AUC_0–40 was significantly greater when ranitidine was administered in pH 5 buffer or in 50% bile into the duodenum compared to the midgut. C _max was significantly different between administration into the duodenum and midgut only when ranitidine was administered in 50% bile. Ranitidine administration in pH 5 buffer significantly decreased AUC_{0– 40} and C _max after administration into the midgut, and AUC_0–40 after administration into the terminal ileum compared to administration with pH 7 buffer or in 50% bile. Bile had no significant effect on AUC_0–40 after ranitidine administration into the duodenum and midgut compared to administration in pH 7 buffer. However, bile significantly increased AUC_0–40and C _max after ranitidine administration into the terminal ileum compared to administration with pH 7 and pH 5 buffer. Conclusions. Results suggest that ranitidine is absorbed from the entire small intestine. However, the terminal ileum is the optimal site of gastrointestinal absorption. Furthermore, bile enhances ranitidine absorption from the terminal ileum.     

诺模图法预测口服给药的吸收速率常数

目的：用已知的达峰时间(tpeak)和消除速率常数(ke)建立诺模法，估算口服给药的吸收速率常数(ka)。方法：根据口服给药的血药浓度—时间曲线曲线方程和tpeak,ka和ke的函数关系，进行数学推导建立诺模图。应用诺模图分析46个药物的ka与数学解析法计算的ka，比较评价诺模图的准确度。用高效液相色谱荧光法检测18位健康志愿者羧甲司坦的血药浓度，将羧甲司坦实测血药浓度与由ka结合其他药代动力学参数的估计血药浓度比较，评估诺模图执行误差。结果：诺模图估算的ka值与解析法计算的ka值接近；MDPE和MDAPE执行误差分别为1．32％，18．15％。结论：本文设计的诺模图准确可靠，执行误差符合临床药代动力学要求。可为制定合理的个体化给药方案提供一个方便快捷的方法。     

Absorption of Polyethylene Glycols 600 Through 2000: The Molecular Weight Dependence of Gastrointestinal and Nasal Absorption

Polyethylene glycols (PEGs) 600,1000, and 2000 were used to study the molecular weight permeability dependence in the rat nasal and gastrointestinal mucosa. Absorption of the PEGs was measured by following their urinary excretion over a 6-hr collection period. HPLC methods were used to separate and quantitate the individual oligomeric species present in the PEG samples. The permeabilities of both the gastrointestinal and the nasal mucosae exhibited similar molecular weight dependencies. The steepest absorption dependence for both mucosae occurs with the oligomers of PEG 600, where the extent of absorption decreases from approximately 60% to near 30% over a molecular weight range of less than 300 daltons. Differences in the absorption characteristics between the two sites appear in the molecular weight range spanned by PEG 1000. For these oligomers, the mean absorption from the nasal cavity is approximately 14%, while that from the gastrointestinal tract is only 9%. For PEG 2000, mean absorption decreases to 4% following intranasal application and below 2% following gastrointestinal administration. Within the PEG 1000 and 2000 samples, however, very little molecular weight dependency is seen among the oligomers. In the range studied, a distinct molecular weight cutoff was not apparent at either site.     

Influence of Absorption Rate,Dosing Frequency,and Intrinsic Pharmacokinetic Profile on Steady-State Drug Concentrations

Pharmaceutical Research -     

Absorption kinetics of oral and rectal flecainide in healthy subjects

Summary The absorption kinetics of different pharmaceutical formulations of orally and rectally administered flecainide have been assessed in a cross-over study in 7 healthy volunteers. The subjects received single doses of flecainide after a washout period of at least one week. A tablet, an oral solution, a rectal solution and a 10 min i.v. infusion during 10 min each containing 100 mg flecainide were administered to the subjects in a randomized order.The mean absolute bioavailability was 98%, 78% and 81% for the rectal and oral solutions and the tablet. The lag time after administration of the oral solution was 0.33 h and it was 0.86 h after the tablet and 0.18 h after the rectal solution. The mean time to the peak serum concentration (t_max) after the rectal solution (0.67 h) was shorter than after either the tablet (4 h) or oral solution (1 h). The maximum serum concentration (C_max) was 0.29 mg · 1^–1 after the rectal solution, 0.14 mg · 1^–1 after the tablet and 0.17 mg · 1^–1 after the oral solution. All the volunteers showed significantly higher serum flecainide concentrations during the first 20 min of the absorption phase after rectal administration of 100 mg flecainide as a solution compared to its oral administration.In conclusion: based on the absolute bioavailability, C_max, t_max, and lag times, rectal administration of flecainide solution gave a better absorption profile than after oral tablet or solution.     

Comparison of Canine and Human Gastrointestinal Physiology

In this review, the gross physiology of the gastrointestinal tract of dogs is compared with that of humans, particularly as it pertains to drug absorption and dosage-form performance. Gastrointestinal (GI) motility and pH are the main parameters considered. Although similar motility patterns and pH profiles prevail in the two species for the most part, there are some differences that could affect the time profile and extent of drug absorption. These include slower gastric emptying in the fed state, faster small intestine transit, and higher and more variable intestinal pH in dogs compared with humans. An attempt is made to identify drug and dosage-form properties that would lead to differences in drug absorption in the two species, e.g., drug physicochemical properties, dosage-form size, and pH dependency of dosage-form release characteristics.     

Site-Differential Gastrointestinal Absorption of Benazepril Hydrochloride in Healthy Volunteers

The absorption of benazepril-HCl (BZPH), an orally active angiotensin-converting enzyme (ACE) inhibitor, in various regions of the gastrointestinal (GI) tract was investigated using an intestinal intubation technique. Thirteen subjects completed this single-dose, three-phase sequential crossover study. The drug (20 mg) was administered either as a 4-hr colonic infusion (COLON) or as a small intestinal infusion (SI) in the first two phases and as an oral bolus solution (ORAL) in the third phase, with a 2-week washout between each treatment. Serial plasma and urine samples were collected for up to 4 days after dosing. BZPH and its active metabolite benazeprilat (BZPL) were determined using a gas chromatography/mass spectrometry method. BZPH was absorbed rapidly into the bloodstream (T _max = 0.5 hr after ORAL). Absorption was also rapid for SI, with a postinfusion half-life (0.57 hr) nearly identical to that for ORAL (0.59 hr). The absorption rate after COLON was much slower (lower C _max and longer T _max) compared to that after SI, and the apparent half-life (1.7 hr) was prolonged. SI delivered 90%, whereas COLON delivered 23%, of the drug into the systematic circulation as compared to ORAL. BZPL was rapidly formed upon drug absorption. The metabolite-to-drug AUC ratios were comparable for SI and ORAL (8.9 vs 9.7), indicating that first-pass metabolism of BZPH was neither saturable nor input rate dependent. The metabolite-to-drug AUC ratio was reduced for COLON (5.0), indicating that the mechanism of absorption of BZPH in the colon may be different than that after SI and ORAL. Urinary recovery data were consistent with plasma data. It can be concluded that COLON delivered a smaller amount of drug at a slower absorption rate to the body than either SI or ORAL.     

豆腐果素缓释微丸的研究.Ⅱ.在大鼠胃肠道的吸收

采用在体灌流法考察了豆腐果素在大鼠胃肠道的吸收情况。根据该结果研制可持续释药12h的缓释微丸。试验结果表明，豆腐果素在大鼠胃、小肠各段均有吸收，在结肠处无吸收。豆腐果素缓释微丸与普通片剂相比，缓释微丸在狗体内的平均滞留时间（MRT）明显延长。     

Regional Gastrointestinal Absorption of the Beta-Blocker Pafenolol in the Rat and Intestinal Transit Rate Determined by Movement of 14C-Polyethylene Glycol (PEG) 4000

The gastrointestinal absorption characteristics of pafenolol following oral administration as a solution in man and rat has previously been found to be a double-peak phenomenon and exhibited dose-dependent bioavailability, despite negligible presystemic metabolism. In both man and rat the first peak appeared approximately 0.5–1 hr postdose and the second, more pronounced peak 3–4 hr postdose. In rat more than 90% of the available dose was absorbed during the second peak. In the present study we investigated the absorption of a solution of pafenolol in rats after intrajejunal and intraileal administration. The resulting blood concentration–time profile of pafenolol exhibited one peak only; the extent of absorption was similar to that observed when the same dose was given orally. The small intestinal transit time of the ¹⁴C-PEG 4000 solution was found to be more than 3 hr. The transit rate was higher in the proximal part of the small intestine compared to the more distal part, where the transit of the solution was staggered. In conclusion, the results of the intestinal transit time investigation and the administrations of pafenolol at different levels of the alimentary tract indicate that pafenolol is a drug with a specific absorption site located in the ileocolonic region.     

Adequacy of Rifampin Absorption after Jejunostomy Tube Administration

It is not always possible to administer antituberculosis pharmacotherapy orally for reasons that may be a direct consequence of tuberculosis itself. To our knowledge, no published literature is available regarding antituberculosis drug absorption via feeding tube. We present the case of a patient with tuberculosis meningitis who required medication administration via percutaneous endoscopic jejunostomy (PEJ) tube. Blood samples were collected during the continuation phase of antituberculosis therapy, immediately before dose administration, and then at 1, 2, 4, and 6 hours after dose administration for quantification of serum rifampin concentrations. Assaying these concentrations by high‐pressure liquid chromatography demonstrated a peak serum rifampin level (C_max) of 18 μg/ml and total rifampin exposure (area under the curve from 0–6 hours [AUC_0–6]) of 50.1 μg/ml. These are high compared with rifampin C_max and AUC_0–6 values reported in patients after oral rifampin administration; C_max tends to range between 4.0–10.5 μg/ml and AUC_0–6 7.0–52.9 μg/ml after oral administration of 600 mg at steady state. Based on our patient's results, therefore, rifampin administered by PEJ tube appears to be well absorbed, with preservation of adequate C_max and AUC values. It is worth noting that this was in the context of drug administration in the fasted state. In the absence of any published evidence of adequate absorption via jejunal feeding tube in the nonfasted state, it would seem prudent to ensure that patients are fasted when rifampin is administered via PEJ tube, just as patients are when oral rifampin is administered. This report represents the first documented evidence, to our knowledge, of adequate rifampin absorption when administered via PEJ tube and provides important reassurance for health care providers, patients, and families facing similar clinical scenarios.     

The Rate and Extent of Oral Bioavailability versus the Rate and Extent of Oral Absorption: Clarification and Recommendation of Terminology

In the literature, the meanings of the terms oral absorption and oral bioavailability of drugs vary greatly. Absorption has been considered to take place at the mucosal membrane of the gastrointestinal (GI) tract. It has also been defined as the process from the site of drug administration to the site of measurement. In the latter definition, the extent of oral absorption depends on the extent of first-pass elimination in the gut wall and liver even though a drug may be completely absorbed from the GI tract. Moreover, these two terms have also been used interchangeably. Inconsistency in the definition of these two terms has led to varying interpretations of these terms among students, researchers and laymen, and such an inconsistency seems undesirable. Apparently because of these inconsistencies, improper correlations between the Caco-2 permeability or intestinal permeability and the oral bioavailability of drugs subject to extensive first-pass effect may have occurred. It is suggested that absorption be defined as movement of drug across the outer mucosal membranes of the GI tract, while bioavailability be defined as availability of drug to the general circulation or site of pharmacological actions. Since transit times (this may range from about 1 min to several hours) across enterocytes, liver, lungs, and the peripheral venous sampling tissue are virtually unknown for all drugs, this factor alone would favor the use of oral bioavailability rate rather than oral absorption rate in all routine studies.     

Sensitivity of Empirical Metrics of Rate of Absorption in Bioequivalence Studies

Purpose. The sensitivity and effectiveness of indirect metrics proposedfor the assessment of comparative absorption rates in bioequivalencestudies [C _max , T _max , partial AUC(AUC _p ), feathered slope (SL _f ), interceptmetric (I)] were originally tested by assuming first-order absorption.The present study re-evaluates their sensitivity performances using themore realistic inverse Gaussian (IG) model characterizing the inputprocess for oral drug administration. Methods. Simulations were performed for both the first-order orexponential model (EX) which is determined by only one parameter, themean absorption time (MAT = 1/k _a ), and the IG model, whichadditionally contains a shape parameter, the relative dispersion of absorptiontime distribution (CV ² _A ). Kinetic sensitivities (KS) of the indirectmetrics were evaluated from bioequivalence trials (error free data)generated with various ratios of the true parameters (MAT and CV ² _A ) of thetwo formulations. Results. The behavior of the metrics was similar with respect tochanges in MAT ratios with both models: KS was low with C _max ,moderate with SL _f and AUC _p , and high with I and T _max followingcorrection for apparent lag time (T _lag ). Changes of the shape parameterCV ² _A , however, were not detectable by C _max , T _max , SL _f , and AUC _p .Changes in both MAT and CV ² _A were well reflected by I with CV ² _A - ratio> 1. I exhibited approximately full KS also with CV ² _A - ratio <1 when a correction was first applied for the apparent lag time. Conclusions. The time profile of absorption rates is insufficientlycharacterized by only one parameter (MAT). Indirect metrics which aresensitive enough to detect changes in the scale and shape of the inputprofile could be useful for bioequivalence testing. Among the testedmeasures, I is particularly promising when a correction is appliedfor T _lag .