Pharmacokinetic Problems in Peritoneal Drug Administration: Tissue Penetration and Surface Exposure

Abstract

Both theory and clinical studies demonstrate that drug concentrations in the peritoneal cavity can greatly exceed concentrations in the plasma following intraperitoneal administration. This regional advantage has been associated with clinical activity, including surgically documented complete responses in ovarian cancer patients with persistent or recurrent disease following systemic therapy, and has produced a survival advantage in a recent phase III trial. Two pharmacokinetic problems appear to limit the effectiveness of intraperitoneal therapy: poor tumor penetration by the drug and incomplete irrigation of serosal surfaces by the drug-containing solution. We have examined these problems in the context of a very simple, spatially distributed model. If D is the diffusivity of the drug in a tissue adjacent to the peritoneal cavity and k is the rate constant for removal of the drug from the tissue by capillary blood, the model predicts that (for slowly reacting drugs) the characteristic penetration distance is (D/k)1/2 and the apparent permeability of the surface of a peritoneal structure is (Dk)1/2. The permeability-area product used in classical pharmacokinetic calculations for the peritoneal cavity as a whole is the sum of the products of the tissue-specific permeabilities and the relevant superficial surface areas. Since the model is mechanistic, it provides insight into the expected effect of procedures such as pharmacologic manipulation or physical mixing. We observe that large changes in tissue penetration may be difficult to achieve but that we have very little information on the transport characteristics within tumors in this setting or their response to vasoactive drugs. Enhanced mixing is likely to offer significant potential for improved therapy; however, procedures easily applicable to the clinical setting have not been adequately investigated and should be given high priority. Clinical studies indicate that an increase in irrigated area may be achieved in many patients by individualizing the dialysate volume and consideration of patient position.

Does Stimulant Therapy of Attention-Deficit/Hyperactivity Disorder Beget Later Substance Abuse? A Meta-analytic Review of the Literature

“…34,35 For example, in preclinical studies with rats, methylphenidate was often administered intraperitoneally at supratherapeutic human dosing equivalence. 9,10 Given that parental administration of methylphenidate exceeds oral dosing, 36,37 the dosing in animals is in excess of the upper limit of therapeutic dosing recommended in humans. 4,6 Our finding of a less robust protective effect of ADHD pharmacotherapy in reducing SUD in adulthood (OR: 1.4) relative to adolescence (OR: 5.8) is noteworthy.…”

Clinical and Pharmacokinetic Characteristics of Intracavitary Administration of Pegylated Liposomal Encapsulated Doxorubicin in Dogs with Splenic Hemangiosarcoma

“…This may be explained by the fact that tissue penetration of most chemotherapeutic drugs is limited to only a few millimeters, IP drug delivery is, therefore, only likely to provide an advantage against surface or implant metastasis, such as the serosal or omental metastasis. [26][27][28] Hepatic metastasis from primary splenic hemangiosarcoma may occur both via direct implant metastasis secondary to tumor rupture but also by hematogenous routes. The intraparenchymal liver metastases are not likely to be exposed to as high initial drug concentration as the superficial implant metastasis.…”

Pharmacokinetic and Pharmacodynamic Analysis of Hyperthermic Intraperitoneal Oxaliplatin-Induced Neutropenia in Subjects with Peritoneal Carcinomatosis

“…Peritoneal fluid and venous blood samples were collected immediately after the oxaliplatin administration and then every 10 min until the end of the peritoneal perfusion. Additional venous blood samples were drawn at 0.25, 0.5, 1, 1.5, 2, 2.5, 3,4,6,8,12,16,20,24, and 28 h after the end of the peritoneal perfusion. All samples were collected in S-monovette® tubes, centrifuged at 3,500 rpm for 10 min and were stored at −80°C until analysis.…”

“…Therefore, drugs rapidly metabolized and/or excreted from the body should be preferred over others as they should decrease the systemic exposure and the risk of toxicity. Consequently, large hydrophilic compounds with limited permeability across an intact peritoneal membrane have been preferred to small lipophilic compounds (12). In this context, cisplatin (13), mytomicin C (14), carboplatin (15), paclitaxel (16), irinotecan (17), and oxaliplatin (18) have been used as chemotherapy agents in HIPEC because their cytotoxic activity is enhanced with hyperthermia.…”