Ocular pharmacokinetic/pharmacodynamic modeling for timolol in rabbits using a telemetry system

We have established an ocular pharmacokinetic/pharmacodynamic (PK/PD) model for a beta-adrenergic antagonist, timolol, after instillation into rabbits. Timolol concentrations were determined by HPLC in the tear fluid, aqueous humor, cornea, and iris-ciliary body after instillation or ocular injection into the anterior chamber of the eye in rabbits. In addition, intraocular pressure (IOP) measurement was performed after instillation of timolol by a telemetry system, which was able to obtain detailed IOP data automatically. The PK/PD parameters were estimated by fitting the concentration-time profiles and the ocular hypotensive effect-time profiles using MULTI (RUNGE) program. The PK model consisted of six compartments and the PD model included aqueous humor dynamics based on an action mechanism of timolol, which causes lowering of IOP by suppressing aqueous humor production. The PK/PD model described well the concentration-time profiles and the ocular hypotensive effect-time profiles after instillation of timolol. This study is the first trial to develop an ocular PK/PD model for timolol after instillation. This model can predict both the drug concentrations in various ocular tissues and the ocular hypotensive effect after instillation of timolol.     

Ocular pharmacokinetic/pharmacodynamic modeling for multiple anti-glaucoma drugs

We have constructed a new ocular pharmacokinetic pharmacodynamic (PK/PD) model for anti-glaucoma drugs to describe ocular hypotensive effects on intraocular pressure (IOP) after instillation of a combination of an alpha(1)-adrenergic antagonist, bunazosin, and a beta-adrenergic antagonist, timolol, into rabbits. This model was constructed by the combination of two ocular PK/PD models for bunazosin and timolol by including aqueous humor dynamics based on both action mechanisms. We also verified the reliability of this model by confirming the drug concentrations in aqueous humor and ocular hypotensive effects after instillation of the drug combination. The aqueous humor concentrations of timolol and bunazosin were determined by an HPLC, and ocular hypotensive effect-time profiles were measured using a telemetry system, which was able to record automatically detailed effects. The combined model could simulate the aqueous humor concentrations of both drugs and the additive IOP-lowering effect after instillation of the combination using the MULTI (RUNGE) program and PK/PD parameters which were obtained from ocular hypotensive effects after instillation of bunazosin alone or timolol alone. The theoretical concentration curves of both drugs in the aqueous humor and the theoretical ocular hypotensive effect curves almost agreed with both the observed concentrations and ocular hypotensive effects after instillation of the drug combination. These results indicate the reliability and usefulness of PK/PD modeling considering aqueous humor dynamics to predict IOP in multidrug therapy. This is the first study to develop a PK/PD model for multidrug therapy for the eye.     

Ocular pharmacokinetics of a novel tetrahydroquinoline analog in rabbit: compartmental analysis and PK-PD evaluation

The elimination kinetics of the pharmacologically active compound 1-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoline (MC4) were characterized along with pharmacodynamic (PD) measurements. Four compartmental models based on ocular anatomy, physiology, and possible absorption and disposition pathways were proposed to model the pharmacokinetic (PK) data in WinNonlin and the best model was chosen based on statistical and goodness-of-fit criteria. A three-compartment physiologic-based PK model with a bidirectional transfer between cornea and aqueous humor and a unidirectional transfer between aqueous humor and iris-ciliary body best described the data. The ocular PD parameters, maximum effect attributed to drug (E(max)) and drug concentration which produces 50% of maximum effect (EC(50)), were estimated with change in intraocular pressure (ΔIOP) as the effect (PD response) in the effect compartment model (PK-PD link model) using aqueous humor concentration-time and ΔIOP-time profiles. The link model better described the effect compartment concentrations than a simple E(max) model that used iris-ciliary body concentration-time data, indicating that there is an apparent temporal displacement between aqueous humor concentration (plasma/central compartment equivalent) and pharmacological effect. A physiologically plausible value of 0.0159 min(-1) was obtained for the drug elimination rate constant (k(eo)) from the effect site to account for equilibration time in the biophase. Hysteresis was observed for the iris-ciliary body, aqueous humor drug concentrations, and effect data, further confirming the utility of the link model to describe the PD of MC4.     

Preparation and ocular pharmacokinetics of ganciclovir liposomes

Ophthalmic liposomes of ganciclovir (GCV) were prepared by the reverse phase evaporation method, and their ocular pharmacokinetics in albino rabbits were compared with those obtained after dosing with GCV solution. The in vitro transcorneal permeability of GCV liposomes was found to be 3.9-fold higher than that of the solution. After in vivo instillation in albino rabbits, no difference was found in the precorneal elimination rate of GCV from liposome vs solution dosing. The aqueous humor concentration-time profiles of both liposomes and solution were well described by 2-compartmental pharmacokinetics with first-order absorption. The area under the curve of the aqueous humor concentration-time profiles of GCV liposomes was found to be 1.7-fold higher than that of GCV solution. Ocular tissue distribution of GCV from liposomes was 2 to 10 times higher in the sclera, cornea, iris, lens, and vitreous humor when compared with those observed after solution dosing. These results suggested that liposomes may hold some promise in ocular GCV delivery.     

Pharmacokinetic prediction of the ocular absorption of an instilled drug with ophthalmic viscous vehicle

We previously developed an in vivo pharmacokinetic model that accounts for the corneal diffusion in albino rabbits and predicts the concentration of beta-blockers in the anterior segments. The purpose of this study is to pharmacokinetically predict the ocular absorption and characterize the systemic absorption of instilled drug with ophthalmic viscous vehicle to assist in its design and evaluation. Tilisolol and carboxymethylcellulose sodium salt (CMC) were used as the model ophthalmic drug and viscous polymer, respectively. After instillation of tilisolol with CMC vehicle in rabbits, the disposition of the drug in tear fluid, aqueous humor, and plasma were determined by HPLC. The ocular and systemic absorption were analyzed by a mathematical model including a diffusion process and a two-compartment model with first-order absorption, respectively. CMC vehicle increased the area under the concentration-time curve (AUC) of tilisolol in the tear fluid and aqueous humor and slightly reduced the AUC in plasma. The concentrations of tilisolol in the aqueous humor after instillation with CMC vehicle were accurately predicted from the tear concentrations by using the in vivo ocular pharmacokinetic model. CMC vehicle improved the ocular delivery of tilisolol.     

Characterization of Ocular Pharmacokinetics of Beta-Blockers Using a Diffusion Model After Instillation

Purpose. To characterize the ocular pharmacokinetics of beta-blockers (timolol and tilisolol) after instillation in the albino rabbit using a mathematical model that includes a diffusion process. Methods. The disposition of fluorescein isothiocyanate-dextran (FITC-dextran, molecular weight 4400), timolol, and tilisolol was determined in tear fluid and aqueous humor after instillation or ocular injection in rabbits. The in vivo penetration parameters were estimated by fitting the concentration-time profiles to the Laplace equations based on a diffusion model using MULTI(FILT) program. Thein vivo permeability of drugs was measured across cornea using a two-chamber diffusion cell. Results. Concentration-time profiles of drugs in the tear fluid after instillation showed a monoexponential curve. Although a monoexponential curve was observed in the aqueous humor concentration of FITC-dextran after injection into the aqueous chamber, timolol and tilisolol showed a biexponential curve. On the basis of these results, anin vivo pharmacokinetic model was developed for estimation of penetration parameters. The in vitro partition parameters were higher than those of the in vivo parameters. Conclusions. The ocular absorption of timolol and tilisolol was characterized using an in vivo pharmacokinetic model and in vivo penetration parameters.     

Oculohypotensive effect of angiotensin-converting enzyme inhibitors in acute and chronic models of glaucoma

We have studied the effects of various angiotensin-converting enzyme (ACE) inhibitors on intraocular pressure (IOP) of rabbits with experimentally induced ocular hypertension and their mechanism of action. Acute ocular hypertension was induced by infusion of 5% glucose (15 ml/kg) through marginal ear vein, whereas chronic glaucoma was induced by injection of alpha-chymotrypsin into the posterior chamber of the eye. IOP was measured by tonometer. All ACE inhibitors were instilled topically in the eye in a sterile solution. The effect of ACE inhibitors also was studied on serum cholinesterase (true and pseudo) and the enzyme ACE in vitro. Enalaprilat, ramiprilat, and fosinopril produced a time-dependent decrease of IOP in both acute and chronic models of ocular hypertension in rabbits. The decrease in IOP was observed for >4 h, and the extent of decrease was comparable to that with both pilocarpine and betaxolol. Prodrugs enalapril and ramipril failed to produced any change in IOP. Losartan also produced a significant decrease in IOP in the chronic model of ocular hypertension in rabbits. All the three ACE inhibitors were found to inhibit ACE activity in aqueous humor. The enzyme cholinesterase was found to be inhibited by enalaprilat, ramiprilat, and fosinopril. However, atropine did not alter the IOP-lowering effect of enalaprilat in rabbits. Indomethacin pretreatment produced slight but significant inhibition of the IOP-lowering effect of enalaprilat in rabbits. Our data suggest that ACE inhibitors enalaprilat, ramiprilat, and fosinopril produce a significant ocular hypotensive effect in acute and chronic models of ocular hypertension in rabbits. Inhibition of ACE in aqueous humor, and in ocular tissues, resulting in reduced angiotensin II formation, could be one of the major mechanisms responsible for the IOP reduction by ACE inhibitors in rabbits.     

Aqueous humor dynamics in anesthetized rats infused with intracameral apraclonidine

We studied the acute effects of the ocular hypotensive drug, apraclonidine (AP), on intraocular pressure (IOP) and aqueous humor dynamics of anesthetized rats during infusion-induced ocular hypertension. Two infusions were made into the anterior chamber of the eye: one was constant at a rate of 0.05 microl/min, the other was cyclic, at a rate of 0.25 microl/min, with the pump on for 4 min, then off for 4 min. Data were processed by complex demodulation and analysis of a second-order transfer function. This permitted separate calculations of resistive components (Ao), i.e., trabecular meshwork and uveoscleral outflows, and residual pressure (RP) estimating nonresistive components, i.e., aqueous synthesis and episcleral venous pressure. A balanced salt solution (BSS) and AP (0. 0005%) were tested. AP markedly delayed the within-group rise in IOP: 20 min for BSS vs. 60 min for AP (p < 0.001). IOP of AP rats was less than control for 100 min (p < 0.05). The infusions raised Ao in both groups (p < 0.05). AP initially had a transient inhibitory effect (p < 0.05). Infusions raised RP in both groups. AP had a strong inhibitory effect for the first 8 cycles (p < 0.05). These data document that the acute effects of AP in this in vivo rat model of ocular hypertension were to delay increases in IOP, mainly by reducing nonresistive components of aqueous humor dynamics. Transient inhibition of resistive mechanisms also occurred.     

Preparation and in vivo ocular absorption studies of disulfiram solid dispersion

Disulfiram, a dimer of diethyldithiocarbamate (DDC) which is a strong radical scavenger, is known to prevent cataract development. However, disulfiram is hardly absorbed from the cornea and its bioavailability is extremely low. In this study, we attempted to prepare disulfiram solid dispersion for the improvement of ocular bioavailability. Solid dispersions of disulfiram were prepared by either an evaporation method or a spray-drying method, using polyvinylpyrrolidone (PVP) as a carrier. Preparations were analyzed by scanning electron microscopy, powder X-ray diffractometry and differential scanning calorimetry, and confirmed to be a solid dispersion. The particle size of the solid dispersion prepared by the spray-drying method was smaller than the preparation by the evaporation method (spray-drying: 3.3+/-0.04 microm, evaporation: 34.3+/-18.0 microm). An in vivo ocular absorption experiment was conducted by instilling solid dispersions to rabbit eye and measuring the DDC in the aqueous humor. After instillation of disulfiram and PVP physical mixture, DDC was not detected in the aqueous humor. On the other hand, DDC appeared in the aqueous humor after the instillation of a solid dispersion. Maximal concentration and the area under the aqueous humor concentration-time curve were greater in the solid dispersion prepared by the spray-drying method than the preparation by the evaporation method. Disulfiram solid dispersion, especially prepared by the spray-drying method, improved ocular bioavailability.     

Characterization of ocular pharmacokinetics of tilisolol after instillation into anesthetized rabbits

The purpose of this study was to characterize the ocular pharmacokinetics of a beta-blocker, tilisolol, after instillation into anesthetized rabbits using a mathematical model including a diffusion process. The samples were analyzed by HPLC. Anesthetized rabbit was used as a model of tear secretion deficiency. Anesthetized rabbits showed higher drug concentration in the tear fluid and aqueous humor after instillation than unanesthetized rabbits. A mathematical model including a diffusion process and in vivo penetration parameters well described the concentrations of tilisolol in the aqueous humor after instillation in anesthetized rabbits.     

比马前列素滴眼液的药理和临床应用

比马前列素是合成的前列酰胺F2α衍生物，通过增加小梁网通道和葡萄膜巩膜通道的房水流出而降低眼内压（IOP），被认为是目前降眼压作用最强的局部抗青光眼药物。主要用于开角型青光眼（POAG）或高眼压症（OHT）的患者，全身不良反应较少。现主要综述该药的药理作用、药动学及临床应用。     

Pharmacokinetic-pharmacodynamic modelling of insulin: comparison of indirect pharmacodynamic response with effect-compartment link models

The pharmacokinetic and pharmacodynamic modelling of insulin has been reported using a combined pharmacokinetic/pharmacodynamic (PK/PD) model, in which a hypothetical effect compartment is linked to a pharmacokinetic compartment. Review of the literature, however, indicated that the recently developed PK/PD models have consisted of an indirect pharmacodynamic response component, but none of them has been applied to the modelling of insulin. To study the relative relevance of the indirect pharmacodynamic response model and the effect-compartment link model in modelling the pharmacokinetics and pharmacodynamics of insulin, regular human insulin was administered intravenously at a dose of 0.1 IU kg(-1) to healthy Yucatan minipigs (after an overnight fasting). The plasma concentrations of insulin were measured by radioimmunoassay at predetermined time intervals, while blood glucose levels were monitored continuously using a glucose monitor. Analysis of the plasma insulin and the blood glucose profiles was performed by fitting with various PK/PD models and the results indicated that all of the 12 sets of plasma insulin data (after normalizing by the basal levels) have been adequately fitted to the two-compartment open pharmacokinetic model (a mean+/-s.e. correlation coefficient of 0.996+/-0.001 was obtained). The mean+/-s.e. correlation coefficient, the weighted residuals sum of squares (WRSS), and the Akaike's information criterion (AIC) were found, respectively, to be 0.935+/-0.008, 624+/-67, and 522+/-9 for the inhibitory indirect pharmacodynamic response model and 0.941+/-0.010, 547+/-63 and 513+/-9 for the stimulatory indirect pharmacodynamic response model, as compared with 0.725+/-0.041, 2309+/-276 and 628+/-10 for the effect-compartment link model. Based on these results, one may conclude that the indirect pharmacodynamic response model is a more appropriate approach for modelling the PK/PD of insulin than the effect-compartment link model.     

Quantifying pharmacodynamic interaction between atenolol and valsartan

We used mathematical modeling in order to determine the pharmacodynamic relationship between antihypertensive drugs atenolol and valsartan, by evaluating their effects on heart rate (HR), systolic blood pressure (SP) and diastolic blood pressure (DP). A group of twelve healthy male volunteers received a single oral dose of 100 mg of atenolol and 160 mg of valsartan, both separately and in combination. Pharmacokinetic (PK), pharmacokinetic/pharmacodynamic (PK/PD) and pharmacodynamic (PD) systems were proposed and PD model of atenolol and valsartan concentration-time profiles and PK/PD model of blood pressure and heart rate effects after administration of single doses of atenolol and valsartan and their combination were constructed. Parameters of PD system, such as gain and mean effect time, were obtained by analysis of PK and PK/PD systems. Modeling of PK and PK/PD systems and their analysis to obtain the PD results could considerably change the view o treatment of individual diseases in terms of greater knowledge of pharmacokinetics and pharmacodynamics of drugs.     

Pharmacokinetic-pharmacodynamic modeling and simulation for bactericidal effect in an in vitro dynamic model

A pharmacokinetic (PK)/pharmacodynamic (PD) modeling strategy to explain the data from an in vitro dynamic model is proposed. Two carbapenem antibiotics, doripenem and meropenem, and three Pseudomonas aeruginosa strains were used as example drugs and strains. The PD model we originally developed to explain the in vitro time-kill data was modified by incorporating bactericidal activities and simulated in vivo PK profiles of the drugs. By employing only one parameter regarding the bactericidal activity from the data at a certain dosage regimen, the bacterial profiles at various dosage regimens could be well simulated for both antibiotics by the PK/PD model. Moreover, simulated bacterial counts for various dosage regimens correlated with time above minimum inhibitory concentration derived from free drug concentrations (fT > MIC) for doripenem. The predicted fT > MIC values to achieve PK/PD endpoints for three strains (static effect: 25.0%, 23.9%, and 39.8%, 2-log killing effect: 28.1%, 29.5%, and 49.6%, 90% maximum killing effect: 36.5%, 46.8%, and 80.7%) were similar to those estimated from free drug concentrations in animal infection models. The proposed in vitro PK/PD model would be useful for simulating bactericidal kinetics in the dynamic model and predicting the human therapeutic target for PK/PD indices estimated from animal infection models.     

Ocular pharmacokinetic models of clonidine-3H hydrochloride

A single topical instillation of clonidine-3H HCl solution (0.2%) was administered to the rabbit eye (30 microliter) in order to study the drug's ocular pharmacokinetics. Seven different tissues and plasma were excised and assayed for drug over 180 min. By 45-60 min pseudoequilibrium is reached for the cornea, iris/ciliary body, and aqueous humor. Thereafter, drug levels in these tissues decline in parallel. The data are fit separately to a physiological model and a classical diffusion model for which seven ocular tissue compartments and a plasma reservoir are constructed for each model. Clearance terms and distribution equilibrium coefficients are determined from the tissue level data and used as parameters in fitting the mass balance differential equations representing the physiological model. The model parameters can also be fit to a 0.4% single dose. In a separate experiment, a topical infusion technique was designed to provide a constant rate input to the cornea until an apparent steady state was reached in aqueous humor at 55 min. Aqueous humor levels were assayed for clonidine over the infusion and postinfusion periods. The physiological model parameters are fit to the topical infusion data and show good agreement between the predicted and experimental data. The classical model is too complex to fit the data to integrated exponential equations primarily because the method of residuals is inadequate in determining a sufficient set of initial estimates. This is overcome by dividing the eight-compartment model into seven fragmental models, each representing one to five compartments. A stepwise procedure is developed in which initial estimates are obtained for each separate fragmental model and refined. The refined parameter values can then be used as initial estimates for the complex model. Differential equations for the complex model are fit simultaneously to tissue levels representing each compartment. By observation, the classical model fit the data more closely than the physiological model. Statistical moment theory is also applied to the topical infusion data to determine ocular pharmacokinetic parameters for clonidine. The calculated values are: corneal absorption rate constant ka, 0.00139 min-1, aqueous humor elimination rate constant k10, 0.0658 min-1; mean residence time MRTd, 35.6 min; apparent steady-state volume of distribution Vss, 0.530 ml; and ocular clearance Qe, 14.9 microliter/min. The fraction absorbed from the single instillation is estimated as 0.0163.     

双氯酚酸钠脂质体的制备及其眼部药代动力学

目的研究双氯酚酸钠脂质体的制备方法并考察其在家兔眼部的药代动力学特征。方法采用逆相蒸发法制备双氯酚酸钠正电荷脂质体。脂质体和滴眼液滴眼后家兔采用高效液相色谱法测定角膜前、角膜和房水中药物浓度。结果制得的脂质体平均粒径为226.5 nm，多分散度为0.214，ζ电位为+18.1 mV，经均匀设计优化处方，包封率可达到63%。0.1%双氯酚酸钠脂质体和滴眼液两种制剂家兔局部滴眼后的药代动力学研究显示，脂质体可延缓药物在角膜前的清除，增加角膜中药物的浓度，药物在房水中半衰期延长，以滴眼液为参比制剂，相对生物利用度为211%。结论双氯酚酸钠正电荷脂质体可以增加药物在角膜前的滞留时间，提高角膜渗透性及药物在眼部的生物利用度，减少滴眼次数。     

Study of the extent of ocular absorption of acetazolamide from a developed niosomal formulation, by microdialysis sampling of aqueous humor

Acetazolamide, a carbonic anhydrase inhibitor is used orally (no topical formulation being available in the market) for the reduction of intraocular pressure (IOP) in patients suffering from glaucoma. Two major reasons responsible for the failure to develop a topically effective formulation of acetazolamide are its low solubility (0.7mg/ml) and its low permeability coefficient. It is generally recognized that topical acetazolamide formulation possessing efficacy similar to that achieved upon oral administration would be a significant advancement in the treatment of glaucoma. In order to enhance the bioavailability of acetazolamide by topical route and to improve the corneal permeability of the drug, the niosomes of acetazolamide were prepared (by reverse phase evaporation method) and coated with Carbopol for the latter's bioadhesive effect. The pharmacodynamic studies showed 33% fall in IOP with the developed formulation, and the effect was sustained for 6h after instillation. The effect compared well with a four times higher concentration of dorzolamide (Dorzox, a topical CAI available in the market. In the present study, the aqueous humor disposition of the drug from the developed bioadhesive coated niosomal formulation (ACZREVbio) is compared with the aqueous suspension of the drug (containing 1% (w/v) Tween 80 as a dispersing agent) at similar concentrations. The concentration of acetazolamide absorbed in the aqueous humor at various times from the control suspension and from ACZREVbio was determined by microdialysis in male albino rabbits. Microdialysis provides a complete concentration versus time profile and hence is an important advance to the regional sampling of tissues. The peak concentration of drug absorbed in the aqueous humor from the ACZREVbio formulation (14.94microg/ml) was almost two times of that obtained with the equivalent amount of acetazolamide control suspension (6.93microg). The results show a significant broadening of peak from 80 to 120min with the concentration of more than 13microg being maintained at these times, for the bioadhesive coated niosomal formulation (ACZREVbio). An important observation was the fact that a high drug concentration of 12.02microg reached immediately, i.e., 20min after instillation of ACZREVbio indicating a high penetration being achieved, while a meagre concentration of only 3.53microg is obtained at 60min after instillation of the control suspension. The aqueous humor disposition indicates peaks and troughs in drug concentration which may be related to the decrease in aqueous humor formation, such that the drug concentration/volume increased at these points.     

Ocular pharmacokinetics of dapiprazole

Dapiprazole is a drug having specific alpha 1 adrenergic blocking properties. Following topical instillation on the eye, it crosses the corneal epithelium reaching high concentrations in the ocular tissue and producing a prompt miotic and hypotensive effect. The high concentration ratio between ciliary bodies and iris versus aqueous humor suggests a peculiar affinity for these structures containing adrenoceptors of the alpha type. The very low concentrations in the plasma, as compared to those after systemic administration, and in the fellow eye indicate that the systemic absorption is negligible.     

Ocular pharmacology of bicyclic hexahydroaporphines

This paper explores the ocular hypotensive actions of bicyclic analogs of hexahydroaporphine (HHA), specifically nor-HHA, in an attempt to shed light on the mechanism(s) by which they lower intraocular pressure (IOP). Studies involving the measurement of IOP and aqueous humor production were conducted in ocular normotensive albino rabbits, while those involving smooth muscle contractility utilized isolated bovine iris. The ability of nor-HHA to produce a sustained drop in IOP is linked to both a functioning adrenergic nervous system and the availability of the products of cyclooxygenase metabolism. Although aqueous flow is not impacted by the bicyclic structures, the significant enhancement of outflow facility points to a probable mechanism of IOP-lowering action. Nor-HHA had no direct contractile or relaxant action on bovine irides, but does cause a concentration-dependent inhibition of carbachol-evoked contractions. This inhibition was reversed by inhibitors of phospholipase A(2) and cyclooxygenase, but not by inhibitors of lipoxygenase, again indicating a role for prostaglandins in the ocular pharmacological action of bicyclic HHAs. Pretreatment with a nitric oxide (NO) scavenger also reversed the ability of nor-HHA to inhibit carbachol-induced contractions, implying a role for NO in the postjunctional actions of HHAs.